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Patients with end-stage isolated polycystic liver disease (PCLD) suffer from incapacitating symptoms because of very large liver volumes. Liver transplantation (LT) is the only curative option. This study assesses the feasibility of LT in PCLD. We used the European Liver Transplant Registry (ELTR) database to extract demographics and outcomes of 58 PCLD patients. We used Kaplan-Meier survival analysis for survival rates. Severe abdominal pain (75%) was the most prominent symptom, while portal hypertension (35%) was the most common complication in PCLD. The explantation of the polycystic liver was extremely difficult in 38% of patients, because of presence of adhesions from prior therapy (17%). Karnofsky score following LT was 90%. The 1- and 5-year graft survival rate was 94.3% and 87.5%, while patient survival rate was 94.8% and 92.3%, respectively. Survival rates after LT for PCLD are good., (© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation.)

Objective: Polycystic liver disease (PLD) is a rare, hereditary, benign disorder. Hepatic failure is uncommon and symptoms are caused by mass effects leading to abdominal distension and pain. Liver transplantation (LTX) offers fully curative treatment, but there is still some controversy about whether it is a relevant modality considering the absence of liver failure, relative organ shortage, perioperative risks and lifelong immunosuppression. The purpose of this study was to review our experience of LTX for PLD and to compare the survival with the overall survival of patients who underwent LTX from 1992 to 2005., Material and Methods: A retrospective study of the journals of 440 patients, who underwent 506 LTXs between 1992 and 2005, showed that 14 patients underwent LTX for PLD. All patients had normal liver function. Three were receiving haemodialysis and thus underwent combined liver/kidney transplantation. One patient had undergone kidney transplantation 10 years earlier., Results: Median follow-up was 55 months. One patient who underwent combined transplantation died after 5.4 months because of multiorgan failure after re-LTX, and one patient, with well-functioning grafts, died of lymphoma after 7 months. At present 12 patients are alive, relieved of symptoms and with good graft function., Conclusions: We conclude that patients treated for PLD by LTX have a good long-term prognosis and excellent relief of symptoms and that LTX might be considered in severe cases of PLD, where conventional surgery is not an option.

Background/aims: The purpose of this study was to assess the outcome of liver retransplantation in adults at our institution and identify the subset of patients in which the outcome was too poor to justify retransplantation., Methodology: Over a 12-year period, we performed 346 liver transplantations in 305 adult patients, and of these, 41 (11.8%) were retransplantations. Survival data were stratified and multivariate analysis was conducted to identify variables associated with poor outcome after retransplantation., Results: The 90-day, 1-year, and 5-year survival rates after liver retransplantation were 65.9%, 62.6%, and 48.2%, respectively. These rates were significantly inferior compared to those following single liver transplantation. Major adverse events affecting patient survival after retransplantation occurred within the first 90 days after surgery. Three independent prognostic variables of patient survival after retransplantation were identified: preoperative coagulation factor, total bilirubin, and the need for preoperative dialysis. Using these variables, we defined a simplified mathematical model available at the time of decision of retransplantation., Conclusions: The present study indicated three important prognostic factors associated with a poor outcome after retransplantation. Based on our newly developed scoring-system estimating patient survival, we suggest that retransplantation must be indicated before the deterioration of more than two organs. These findings should assist in the decision process for liver retransplantation in adult patients.

Background/aims: The results of liver transplantation for Budd-Chiari syndrome (BCS) are poorly known and the role and timing of the procedure are still controversial. The aim of this study was to investigate the results of transplantation for BCS, focusing on overall outcome, on prognostic factors and on the impact of the underlying disease., Methods: An enquiry on 248 patients representing 84% of the patients transplanted for BCS in the European Liver Transplantation Registry between 1988 and 1999., Results: Of the 248 patients, 70.4% were female and 29.6% male. The mean age was 35.7 years. The overall actuarial survival was 76% at 1 year, 71% at 5 years and 68% at 10 years. 77% of deaths occurred in the first 3 months: 47% were due to infection and multiple organ failure, and 18% to graft failure or hepatic artery thrombosis. Late mortality (>1 year) occurred in nine patients, due to BCS recurrence in four of them. The only pre-transplant predictors of mortality on multivariate analysis (Cox) were impaired renal function and a history of a shunt., Conclusions: Liver transplantation for BCS is an effective treatment, irrespective of the underlying cause, and should be considered before renal failure occurs.

Background: Graft loss after liver transplantation remains a significant problem, especially in pediatric patients. The aim of this study was to assess our initial series of pediatric liver transplantation and to identify the risk factors that influence graft outcome., Methods: The first 51 transplantations were analyzed retrospectively. All transplantations were stratified into three groups according to graft type (full-size, reduced-size, and living-related-donor graft). Survival data of the grafts were stratified and multivariate analysis conducted with respect to preoperative and surgical factors., Results: Seventeen of all the transplants were full-size grafts and 34 technical-variant grafts (27 reduced-size grafts from cadavers and 7 living-related-donor grafts). The overall graft survival rates were 65, 62 and 53% at 1, 3 and 5 years, respectively. Twenty-three of 51 grafts (45%) were lost. Poor status of the recipients (hospitalization or intensive care unit care before surgery), a retransplanted graft, and a reduced-size graft were independent risk factors for graft failure. With experience, overall graft survival has improved significantly and the differences in graft survival between graft types have disappeared., Conclusions: To improve graft survival after pediatric liver transplantation, the timely referral of potential recipients to the transplant team and employing a meticulous technique during the operation, particularly for the technical-variant graft, are required.

Obesity is increasing in the western world at an epidemic rate. The USA results in obese patients undergoing orthotopic liver transplantation (OLT) are divergent, and so far no European experience has been reported. This study was designed to determine if obesity is a risk factor for mortality and morbidity in OLT in a medium-size European center. In a retrospective study of the records of 365 consecutive patients who had undergone OLT from 1990 to 2003, 20 obese patients [body mass index (BMI) > 30 kg/m2] were identified. Their data were compared with those of the nonobese (BMI < 30 kg/m2) patients operated immediately before. There were no differences in demographic data, diagnosis leading to OLT, United Network of Organ Sharing (UNOS) classification, Child-Pugh score, or preoperative morbidity. The groups were also comparable concerning donor data, duration of operation, use of blood products, intensive care unit (ICU), or hospital admission. Mortality was, however, significantly increased in the obese group (P = 0.01). Our study clearly demonstrates an increased mortality in obese patients undergoing OLT and the relative scarcity of organs taken into account, it seems reasonable to consider obesity as a relative contraindication to OLT.

Background/aims: Hepatobiliary malignancies are frequently seen in primary sclerosing cholangitis (PSC) and they complicate the evaluation of patients and timing of liver transplantation., Methods: Data from all Nordic PSC patients listed for liver transplantation during 1990-2001 were recorded prospectively. Predictors of hepatobiliary malignancy and patient survival rates have been analysed., Results: Hepatobiliary malignancy was found in 52/255 (20%) patients accepted to the waiting list. Recent diagnosis of PSC, no ursodeoxycholic acid (UDCA) treatment, clinical suspicion and previous colorectal-cancer were predictors of malignancy. Among 89 patients with a strong suspicion of malignancy prior to acceptance, 35 (39%) had confirmed malignancy. A clinical suspicion had been raised in 35/52 (67%) patients with malignancy. Malignancy was found in 31/223 patients who received a liver allograft. The 1-, 3- and 5-year patient survival rates following transplantation for patients with PSC and cholangiocarcinoma were 65, 35 and 35%, respectively., Conclusions: Hepatobiliary malignancy is suspected in 1/3 of the PSC patients and found in 1/5. Although cholangiocarcinoma is regarded as a contraindication to liver transplantation (LTX), PSC patients with cholangiocarcinoma had a 35% 5-year survival following transplantation.

Background: Primary sclerosing cholangitis (PSC) is the most common indication for liver transplantation in the Nordic countries. Because these patients are difficult to evaluate with regard to timing of liver transplantation, it is important to establish predictors of post-transplant survival., Methods: Data from two groups of patients receiving liver allografts during 1982-2001 were recorded: (a) PSC patients and (b) comparison patients. Outcome following transplantation has been recorded for all patients. Regression analyses have been performed for PSC patients to analyse predictors of patient and graft survival., Results: A total of 245 PSC and 618 comparison patients received a first liver allograft in the period 1982 until the end of the study. The overall 1-, 3- and 5-year patient survival rates were 82%, 77% and 75%, and 80%, 77% and 74% in the PSC group and comparison group, respectively. Survival following transplantation has increased with time in both the PSC and the comparison group. Recent year of transplantation, no previous hepatobiliary surgery and a lower MELD score were predictors of survival following transplantation for PSC patients. PSC patients had a higher rate of re-transplantations (13% versus 8%, P = 0.01). Predictors of re-transplantation in PSC patients were an episode of early rejection and vascular thrombosis., Conclusion: In PSC patients, year of transplantation, previous hepatobiliary surgery and MELD score are predictors of survival following transplantation and these patients are more frequently in need of re-transplantation compared to the comparison group.

Primary sclerosing cholangitis (PSC) is a common indication for liver transplantation, but evaluation of patients and timing of liver transplantation remain as major problems. Data from PSC and control patients listed for liver transplantation from 1990 through 2000 in the Nordic countries were recorded prospectively. Outcomes from the waiting list and after transplantation have been recorded for both groups. For PSC patients, regression analyses have been performed to analyze predictors of outcome. A total of 255 PSC and 610 control patients were accepted on the liver transplantation waiting list from 1990 to 2000. In the PSC group, 223 patients (87%) received a first liver allograft, and 32 patients (13%) died without transplantation. The corresponding figures for the control group were 89% and 10%. For PSC patients, the 5- and 10-year survival from the time of acceptance was 68% and 58%, respectively. A higher Model for End-Stage Liver Disease score and a shorter duration of PSC predicted death on the waiting list for PSC patients. PSC is a frequent indication for liver transplantation. In our material, serum bilirubin or Model for End-Stage Liver Disease score and PSC duration are predictors of outcome including survival of the waiting list.

Background: Interindividual variability in dosage requirements of the calcineurin inhibitor immunosuppressive agents cyclosporine and tacrolimus after liver transplantation may result from differences in the CYP3A activity of the liver graft. Early postoperative erythromycin breath test (ERMBT) is an in vivo measure of graft CYP3A activity. This study evaluates the usefulness of an early postoperative ERMBT in predicting early morbidity in liver transplant recipients., Methods: In 26 liver transplant recipients, ERMBT was performed within 2 hr after transplantation. Main end points were the occurrence of cyclosporine and tacrolimus nephrotoxicity, episodes of early graft rejection, early graft function, and graft survival., Results: Cyclosporine and tacrolimus nephrotoxicity were associated with low postoperative ERMBT values (mean 0.63%+/-0.25% 14C/hr vs. 1.35%+/-0.84% 14C/hr, P=0.02). No significant association between early graft rejection and ERMBT values was demonstrated. There was a significant inverse correlation between postoperative ERMBT values and the time to normalization of international normalized ratio as a measure of early graft function (r=-0.78, P<0.001). Graft loss was associated with low postoperative ERMBT values (0.21%+/-0.15% 14C/hr vs. 1.09%+/-0.72% 14C/hr, P=0.002)., Conclusion: An early postoperative ERMBT may be useful in predicting the development of cyclosporine and tacrolimus nephrotoxicity, severe graft dysfunction, or even graft loss in liver transplant recipients when calcineurin inhibitors are administered according to protocols. Whether ERMBT results may be used to individualize dosage of calcineurin inhibitors needs to be explored.

Background: Survival after liver transplantation for fulminant hepatic failure has been reported to be less favorable than survival for patients with chronic liver diseases., Methods: We have studied all patients (n=229) undergoing highly urgent liver transplantation from 1990 to 2001 in the Nordic countries. The impact of patient and donor characteristics, with emphasis on donor-recipient ABO matching (identical, compatible, incompatible), has been studied., Results: One-year and 3-year patient survival rates were 73% and 70% for the total period and 86% and 78% for the last 4-year period. Patients receiving an ABO-compatible liver allograft had significantly lower patient survival rates than those receiving an ABO-identical donor organ (1-year patient survival rates 66% of vs. 79%, P=0.03). Graft survival rates varied less (1-year graft survival rates of 64% vs. 74%, P=0.09). Patients receiving an ABO-incompatible liver allograft had patient survival rates of 70% at 1 year and 60% at 3 years but low graft survival rates (40% and 30% at 1 and 3 years). In a multiple regression analysis, significant independent predictors of poor patient survival were early year of transplantation, ABO-compatible donor, high donor age, and waiting time more than 3 days and less than 9 days., Conclusion: Survival after highly urgent liver transplantation has improved and is comparable to that observed in patients receiving a liver allograft because of chronic liver disease. Patients receiving an ABO-identical donor organ had significantly higher patient survival rates compared with those receiving an ABO-compatible donor liver.

Fulminant hepatic failure is a common indication for liver transplantation. Outcomes of patients listed for a highly urgent liver transplantation have been studied, with special emphasis on etiology of the liver disease, clinical condition, and ABO blood type. Data have been collected from the Nordic Liver Transplantation Registry. All Nordic patients listed for a highly urgent primary liver transplantation during a 12-year period have been included. Of the 315 patients listed for a highly urgent liver transplantation, 229 (73%) received a first liver allograft, 50 patients (16%) died without transplantation, and 36 patients (11%) were permanently withdrawn and survived. In 43% of the patients, no definite etiology of the liver failure could be established. Paracetamol intoxication was the most frequent specific indication for listing. Patients with blood type A had no significant shorter waiting time (3.8 v 6.6 days; P =.1) but a higher rate of transplantation (82% v 66%, P =.006) as compared with blood type O patients. In a multivariate analysis, paracetamol intoxication remained the single independent predictor of an outcome without transplantation. In conclusion, a high transplantation rate was observed among patients listed for a highly urgent liver transplantation because of fulminant hepatic failure. Blood type O patients had a lower chance of receiving a liver allograft. Patients with paracetamol intoxication had both a higher mortality without transplantation and a higher withdrawal rate attributable to improved condition.

Over the last two decades, orthotopic liver transplantation (OLT) has become an established treatment for acute and chronic liver failure. OLT impacts not only on survival, but also on health-related quality of life. This study was undertaken to describe the self-rated health of Danish liver transplant recipients, compare their self-rated health against that of the general population, and to investigate associations between sex, age, diagnosis, time after OLT, and postoperative physical function and fatigue. All adult surviving liver transplant recipients who underwent OLT in Copenhagen, Denmark, from 1990 to 1998 (n = 154) were contacted by mail and asked to complete a self-administered questionnaire. The questionnaire contained the 36-Item Short Form Health Survey, the Multidimensional Fatigue Inventory, the Hospital Anxiety and Depression Scale, and questions on marital status, education, and work. The response rate was 84.4% (n = 130). Liver transplant recipients reported poorer self-rated health than the general population in physical, but not in mental, health areas. One health aspect, fatigue, was investigated in great detail. This study found that liver transplant recipients experienced physical, rather than mental, fatigue. Diagnosis was found to be a predictor of postoperative physical function and fatigue because patients with an alcoholic or cryptogenic cirrhosis background had significantly poorer physical function and experienced more physical fatigue than liver transplant recipients with other diagnoses. Work status and survival time after OLT had significant effects on postoperative physical function and fatigue. Working and having undergone transplantation 4 to 5 years previously were associated with significantly better physical function and less physical fatigue than not working and having undergone transplantation 1 to 3 years previously. This study suggests that liver transplant recipients experience physical, rather than mental, impairment and fatigue and that diagnosis, work status, and survival time after OLT are associated with physical function and fatigue.

Background: Interindividual variation in the pharmacokinetics of the immunosuppressive agents cyclosporine (INN, ciclosporin) and tacrolimus may result from differences in the activity of cytochrome P4503A (CYP3A). The erythromycin breath test is an in vivo assay of hepatic CYP3A activity, but the method has never been directly validated. The aim of the study was to investigate whether an early postoperative erythromycin breath test correlated with the hepatic CYP3A protein level and catalytic activity in liver transplant recipients., Methods: In 18 liver transplant recipients, the erythromycin breath test was performed within 2 hours after transplantation. A graft biopsy was obtained during surgery and analyzed for the CYP3A protein level by Western blotting and for CYP3A activity with erythromycin demethylation and testosterone 6beta- hydroxylation assays., Results: The erythromycin breath test values ranged from 0.14% to 1.65% of carbon 14 per hour, and the CYP3A protein level ranged from 732 to 7822 as measured by optical density. The in vitro catalytic activity determined by the erythromycin demethylation assay ranged from 94 to 902 disintegrations per minute per 5 minutes per milligram of protein, and the activity determined by testosterone 6beta-hydroxylation ranged from 0.030 to 0.627 nmol per minute per milligram of protein. Significant correlation was demonstrated between the erythromycin breath test and both the erythromycin demethylation (Spearman correlation coefficient: R = 0.76, R (2) = 0.57; P =.0004) and the testosterone 6beta-hydroxylation (Spearman correlation coefficient: R = 0.79, R (2) = 0.63; P =.0001) assays. The erythromycin breath test also correlated with the CYP3A protein level (Spearman correlation coefficient: R = 0.60, R (2) = 0.36; P =.01)., Conclusion: Our data support the erythromycin breath test as a specific in vivo assay of CYP3A activity in humans. The test is applicable in liver transplant recipients in the early postoperative phase. Future studies should evaluate the clinical usefulness of an early postoperative erythromycin breath test as a predictor of cyclosporine-tacrolimus pharmacokinetics in liver transplantation.

Liver transplantation was previously only offered to patients under 60 years of age. We have analyzed the outcome after acceptance on the waiting list and after liver transplantation of patients over 60 years old. A total of 150 patients over 60 years old were listed for a first liver transplantation during 1990-1998. The annual number increased throughout the period. Primary biliary cirrhosis, primary sclerosing cholangitis, and acute hepatic failure were the most frequent diagnoses. A total of 119 patients received a first liver allograft. The patient 1-year survival was 75% and 3-year survival 62%, which was not significantly lower (P = 0.21) than that of the younger patients. When correcting for year of transplantation, the survival was, however, moderately but significantly lower than among the younger patients. Survival among those > 65 years (n = 38) did not differ from that of patients 60-65 years of age (n = 81). We conclude that an increasing number of patients over 60 years old can be listed for liver transplantation and receive a liver allograft with highly satisfying results.

Background: We determined whether the coupling between cerebral blood flow (CBF) and oxygen metabolism (CMRO2) is preserved during liver transplantation. Because of cerebrovascular dilatation, we hypothesized that cerebral metabolic autoregulation is impaired, because CBF becomes uncoupled from CMRO2 during the reperfusion phase of the operation., Materials and Methods: In a prospective study, 13 patients (8 women, median age 46, range 21-6) with liver failure (10 with end-stage chronic liver disease and 3 with acute liver failure) were enrolled. Catheters were placed in a femoral artery and in the internal jugular vein for calculation of the cerebral arteriovenous oxygen content difference (AVDO2). CBF was recorded by the 133Xenon injection technique, and by transcranial Doppler sonography determined mean flow velocity (Vmean) in the middle cerebral artery. The CMRO2 was calculated as the AVDO2 times CBF and the cerebrovascular resistance (CVR) as the mean arterial pressure to CBF ratio. An index of large cerebral artery diameter was expressed by the CBF to Vmean ratio., Results: From induction of anesthesia to the anhepatic period, CBF decreased from a median of 47 (interquartiles 31-55) to 41 (37-48) ml 100 g(-1) min(-1), whereas the CMRO2 remained unchanged (1.3 [0.9-2.5] vs. 1.7 [0.9-2.3] ml 100 g(-1) min(-1)). In the reperfusion phase, the CBF increased to 51 (45-54) ml 100 g(-1) min(-1), whereas the CMRO2 remained unchanged at 1.1 (1.0-2.5) ml 100 g(-1) min(-1). The CVR decreased from 2.0 mm Hg (1.4-2.1) to 1.4 (1.1-1.8) mm Hg(-1) min 100 g ml. In the anhepatic phase, mean arterial pressure decreased from 92 mm Hg (84-98) to 85 (80-92) mm Hg and at reperfusion it was 80 (71-105) mm Hg. From the anhepatic to the reperfusion phase, the CBF increased 7% (0 to 26) for each mm Hg concomitant increase in PaCO2. The CBF to Vmean ratio remained stable (1.0 [0.8-1.2] vs. 0.9 [0.7-1.1] ml 100 g(-1) min(-1) cm(-1) sec)., Conclusion: During the reperfusion phase of liver transplantations, cerebrovascular dilatation uncouples cerebral oxidative metabolism from blood flow. The increase in CBF is beyond what can be explained by changes in arterial carbon dioxide tension and arterial pressure.

Serum levels of the actin scavenger Gc-globulin (group-specific component, vitamin D-binding protein), a member of the albumin multigene family, are decreased in severe liver disease but have not been evaluated in relation to liver transplantation. We measured Gc-globulin and Gc-globulin-actin complex ratio daily for 2 weeks after transplantation in 17 patients with end-stage liver disease. Before transplantation, Gc-globulin levels were significantly less in the patients than in healthy controls (235 +/- 106 v 340 +/- 35 mg/L, respectively; P<.001), whereas complex ratio level was in the normal range. Five patients (group N) had pretransplantation Gc-globulin values within the normal range (mean +/- 2 SD), and 12 patients had subnormal values (group S). In group N, mean Gc-globulin levels posttransplantation remained stable at a lower level than before transplantation but still within normal range. In this group, cold ischemia time correlated inversely with Gc-globulin levels on day 2 (r = -0.88; P <.05). In group S, normal mean levels were reached at a mean of 11 days after transplantation. However, almost half these patients had subnormal Gc-globulin levels at day 14. Complex ratio levels remained normal in the study period in both groups. Prothrombin index levels (plasma coagulation factors II, VII, and X) were identical in both groups and returned to normal 7 days posttransplantation, whereas plasma albumin levels were less than normal in both groups and further decreased after transplantation. In conclusion, the maintenance (group N) or reestablishment (group S) of serum Gc-globulin to normal levels occurred in the early posttransplantation course in the same time frame as the prothrombin index. Gc-globulin synthesis seems unrelated to albumin synthesis. A prolonged cold ischemia time may cause reduced Gc-globulin levels early after transplantation.

Orthotopic liver transplantation (OLT) has become a frequently used treatment for end-stage liver disease and acute liver failure, and liver function is markedly improved after transplantation. However, no studies have investigated the development in physical capacity after OLT. On this basis, the aim of the present study is to study the influence of OLT on physical fitness during the first postoperative year. Twenty-three men with a mean age of 45.1 years (range, 24 to 62 years) and 15 women with a mean age of 44.6 years (range, 21 to 62 years) were included in the study. Preoperative maximal oxygen uptake (VO2max) during graded ergometer bicycling, isokinetic knee extension/flexion moments, and functional performance (i.e., 6-minute walking distance and standardized transfers and squats) was measured. Preoperative fitness and strength was 40% to 50% less than expected in the age-matched general population. Post-OLT, all patients underwent a supervised exercise program for 8 to 24 weeks. Follow-up data showed a significant increase in all tested physical performance parameters after OLT. Six months post-OLT, VO2max had increased 43%; knee strength, 60% to 100%; and functional performance, 22% to 27%. One year postsurgery, general health was improved and perceived as excellent or good in all patients. All patients were independent in activities of daily living, and the level of physical activity increased after OLT. No further improvement in either physical performance parameters or self-assessed parameters was seen beyond 6 months after OLT. In conclusion, these findings indicate that OLT combined with a supervised post-OLT exercise program improves physical fitness, muscle strength, and functional performance in individuals with chronic liver disease.

Background: Liver transplantation has become an established therapeutic option for patients with life-threatening liver disease. The aim of the present study was to analyse the results of and developments in liver transplantation in the Nordic countries during a 15-year period., Methods: Data on all patients receiving a liver allograft in the Nordic countries during 1982-98 and waiting list data for all patients listed for a liver transplantation after 1989 were obtained from the Nordic Liver Transplantation Registry., Results: A total of 1485 first liver transplantations were performed during 1982-98. The annual number of first liver transplantations increased steadily up to 1993, thereafter remaining around 150-170 per year. There are major differences between countries both in the number of transplants adjusted to populations performed per year, with more than twice as many performed in Sweden as in Norway, and in the relative distribution of patients in accordance with diagnosis. The number of patients more than 60 years old increased and comprised 13%-14% of the total patient population during 1996-98. Primary biliary cirrhosis, primary sclerosing cholangitis, acute hepatic failure, malignant liver disease, and alcoholic cirrhosis are the five most frequent diagnoses. The over-all 1-year patient survival probability has increased from 66% among patients receiving a transplant in 1982-89 to 83% in 1995-1998. The waiting time remains stable, with a median waiting time of 35 days during 1990-98. The mortality of patients while on the waiting list is 7.4% and is not increasing., Conclusion: Results of liver transplantation in the Nordic countries are very similar to those obtained in other countries. Waiting time and mortality remain low. There are, however, major differences between the countries both as to the number of transplantations performed and as to distribution of diagnoses.

Background: Orthotopic liver transplantation is possible even in the presence of recipient portal vein thrombosis, provided that hepatopetal portal flow to the graft can be restored. On rare occasions this is not possible due to diffuse thrombosis of the portal venous system. In these cases, successful liver transplantation has been considered impossible. Portocaval transposition was introduced in the pretransplantation era to study the effect of systemic venous flow on the liver and has been used in three patients for the treatment of glycogen storage disease. We used portocaval hemitransposition (portal perfusion with inflow from the inferior vena cava) in liver transplantation when portal inflow to the graft was not feasible. We are reporting the collective experience of nine patients from four liver transplant centers., Methods: Cavoportal hemitransposition was used in nine patients. In seven of these cases, the technique was used during the original transplant (primary group). In two cases, it was used after the portal inflow to the first transplant had clotted (secondary group)., Results: Five of seven patients in the primary group are alive after intervals of 6-11 months. The two patients in the rescue group died. In the successful cases, liver function and histology were indistinguishable from those of conventional liver transplantation. Ascites disappeared within 3-4 months and the patients were able to return to their normal activities. Postoperative variceal bleeding necessitated splenectomy and gastric devascularization in one case and splenic artery embolization in another case. Bleeding was controlled in both these cases. Splenectomy and gastric devascularization were performed prophylactically in one patient with a history of variceal bleeding in order to prevent this complication after transplantation., Conclusion: Portocaval hemitransposition maybe useful in liver transplantation when hepatopetal flow to the liver graft cannot be established by other techniques. Rescue after failure of conventional technique was not possible in two patients.

After reperfusion of a liver graft, transcranial Doppler determined middle cerebral artery flow velocity, increases more than expected from the arterial carbon dioxide tension (PaCO2). We evaluated if this indication of cerebral hyperperfusion is reflected in the jugular oxygen saturation (SjO2) (n = 31) and oxygen saturation (ScO2) (near-infrared spectrophotometry, n = 22). From the dissection phase to the anhepatic phase SjO2 71.0% (range 62.3%-78.5%), ScO2 70% (range 65%-77%), and PaCO2 34.9 mm Hg (range 30.8-38.3) remained statistically unchanged. In contrast, during the early reperfusion phase, SjO2 increased to 77.0% (71.4%-83.0%) (P < 0.01) and the ScO2 to 75% (68%-80%) (P < 0.05) as PaCO2 increased to 37.5 mm Hg (34.8-41.9) (P < 0.001). Notably, SjO2 also increased at reperfusion from 71.6% (66.5%-78.0% mm Hg) to 80.0% (76.8%-84.8%) in the four patients in whom PaCO2 decreased at reperfusion from 37.6 mm Hg (36.8-39.5) to 34.0 mm Hg (32.3-36.8). If the changes in SjO2 after reperfusion of the grafted liver should be explained as a reflection of changes in cerebral blood flow, in response to PaCO2, it would indicate a highly accentuated CO2 reactivity of 13%/mm Hg. The results support that cerebral blood flow and, in turn, oxygenation increase after reperfusion because the grafted liver liberates a vasodilating substance(s).

Inferior vena cava (IVC) clamping during liver transplantation causes venous congestion in the splanchnic and IVC beds. A venovenous bypass relieves congestion and improves cardiac output (CO), but the bypass flow required for adequate drainage of the vascular beds is controversial. In this study we evaluated the bypass flow necessary to compensate for the IVC clamping. Lower body impedance (BI) is inversely related to tissue fluid content and was used to reflect congestion. A venovenous bypass was successfully applied to 59 of 62 patients. BI was measured across the left buttock and related to bypass flow, CO, bypass flow ratio (bypass flow/CO before IVC clamping; n = 62), and right femoral venous pressure (n = 8). The bypass flow was 1.7 (0.0-3.0) L.min-1 (median and range). BI decreased (delta BI; -2.2 [-10.3-1.1)] omega) as the femoral venous pressure increased (29 [21-49] mm Hg; r = -0.81; P < .05), and the femoral venous pressure correlated inversely to bypass flow (r = -0.35; P < .01). The change in CO at IVC clamping (delta CO; -2.3 [-6.3-1.6] L.min-1) related to bypass flow ratio (0.25 [0-0.51]; r = 0.57, P < .01), whereas delta BI related only minimally to bypass flow or bypass flow ratio (r = 0.37; P < .05). In conclusion the median bypass flow of 1.7 L.min-1 was too small to prevent fluid accumulation in the lower caval region, and extrapolation of data suggests that bypass flow should have approached 3.5 L.min-1 or 50% of CO in order to prevent fluid accumulation in the lower caval region. However the minimal correlation between lower BI and bypass flow indicates that bypass flow per se is not the only determinant of lower body fluid accumulation.

Portal venous and hepatic arterial flow was measured intraoperatively in the 70 most recent patients undergoing liver transplantation in our institution. Impaired graft flow due to vascular abnormalities was detected in six patients. One patient suffered from arterial steal due to stenosis of the recipient celiac trunk with blood shunting from the hepatic to the splenic artery. Ligation of the recipient hepatic artery restored the arterial graft flow. In two patients we found reduced portal venous flow due to large portosystemic collaterals. The collaterals accountable for the impaired portal flow were identified and ligated, which restored portal venous graft flow. Excessive sensitivity of the portal venous flow to the position of the graft was found in a 6-month-old boy. Portal venous flow varied considerably, depending upon the position of the graft, and intraoperative flow measurement allowed the best position of the graft to be identified. Two patients developed arterial thrombosis in the early postoperative course. Immediate laparatomy with thrombectomy resulted in good, palpable pulsation in the graft artery in both patients. Intraoperative flow measurement demonstrated satisfactory arterial flow in one patient, whereas there was no net flow in the other patient's graft artery. Pulsation in this patient was caused by blood oscillating in and out of the liver. In conclusion, we find that causes of primary graft dysfunction due to technically flawed reperfusion of the graft can be identified and alleviated by intraoperative measurement of the flow in the graft vessels.

Twenty-five liver transplant patients were administered liquid microemulsion cyclosporine (Neoral, 5 mg/kg b.i.d.) via a nasogastric tube until they could take oral medication. The first dose was given within 6 hr after surgery. Adequate trough levels of cyclosporine were obtained from the first postoperative day. The total exposure to the drug was low on the first postoperative day, but a significantly improved pharmacokinetic profile with a high maximal concentration and a low time to maximal concentration was found from the second postoperative day. The absorption from Neoral increased during the first week. After 1 week, a low within-patient variation coefficient for dose-adjusted cyclosporine trough levels was found (17%). The between-patient variation coefficient was low during the whole postoperative period (31%). We conclude that in liver transplant patients adequate immunosuppressant blood levels of cyclosporine can be obtained in the immediate postoperative period using Neoral without the need to go to the intravenous form of the drug.

The impact of liver transplantation on the survival in fulminant hepatic failure was evaluated in a retrospective study including 87 patients admitted to Rigshospitalet over a three and a half year period before and a three and a half year period after the Danish liver transplantation programme was started. The number of admissions increased by 178% in the second period. Fifty-two percent of the patients had acetaminophen induced liver failure, which over the last seven years has become the most common cause of severe acute liver disease in Denmark. In about half of the patients high volume plasmapheresis was used as liver-assist either alone or in combination with liver transplantation. Three patients in grade 4 hepatic coma (one with Hepatitis B, two with acetaminophen intoxication) were withdrawn from the waiting list for emergency liver transplantation after high volume plasmapheresis due to recovery. In patients with an estimated survival chance of less than 5-10% liver transplantation was performed with a survival rate of 60%. The survival rate for the non-liver transplanted patients was 49% in the same period compared to 30% in the three and a half year period before liver transplantation started.

Oxidative damage is thought to play an important role in ischemia/reperfusion injury, including the outcome of transplantation of the liver and intestine. We have investigated oxidative DNA damage after combined transplantation of the liver and small intestine in 5 pigs. DNA damage was estimated from the urinary excretion of the repair product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). In the first 1-3 hr after reperfusion of the grafts, 8-oxodG excretion was increased 2.9-fold (1.7-4.1; 95% confidence intervals; P < 0.05). A control experiment included sham surgery with clamping of the suprarenal inferior caval vein in 2 pigs during steady state infusion of 8-oxodG. While the caval vein was clamped, the urinary excretion of 8-oxodG was almost blocked, whereas after removal of the clamp, the excretion returned to and did not exceed the preclamp levels. In a separate experiment with 2 pigs, the elimination of injected 8-oxodG was shown to adhere to first-order kinetics with a clearance and a terminal elimination half-life of approximately 4 ml min-1 kg-1 and 2 1/2 hr, respectively. The injected dose was completely excreted into the urine within 4 hr. It is concluded that substantial oxidative damage to DNA results from reperfusion of transplanted small intestine and liver in pigs, as estimated from the readily excreted repair product 8-oxodG.

Transplantation of the liver results in surgical denervation of the organ. However, it is not known whether and to what extent sympathetic reinnervation occurs postoperatively in the transplanted human liver. Thirty-two liver biopsies (right lobe) were obtained from 13 liver-transplanted patients 1, 3, 6, 12 or 30 months after transplantation and 11 biopsies were obtained from 11 non-transplanted subjects with normal liver tests. The concentrations of the sympathetic neurotransmitter norepinephrine and of epinephrine were determined in liver tissue homogenates. The concentration of norepinephrine was 0.019 +/- 0.05 nmol. g wet liver tissue-1 (mean and SE, n = 32) in the transplanted patients, which was only 1% of the concentration in biopsies from control subjects (2.180 +/- 0.420 nmol.g wet liver tissue-1). The hepatic norepinephrine concentration did not increase significantly over time in liver-transplanted patients during the observation period (0.015 +/- 0.008 nmol.g wet wt-1 (1 month post) (n = 8) vs. 0.024 +/- 0.018 nmol.g wet wt-1 (12 months post) (n = 6) and 0.012 +/- 0.006 nmol.g wet wt-1 (30 months post) (n = 5)) (p < 0.05). The liver tissue concentration of epinephrine was markedly lower in liver-transplanted subjects (0.01 +/- 0.003 nmol.g wet tissue-1) than in control subjects (0.04 +/- 0.007 nmol.g-1) (p < 0.01). This study indicates that within the first years after transplantation, there is no evidence of sympathetic liver nerve reinnervation in liver-transplanted patients.

During the first 12 months of the Danish Liver Transplantation program, which began in October 1990, 21 transplantations were performed in 11 women, six men and three children. One patient required a retransplant. Fourteen operations were performed electively and six patients were transplanted for acute and subacute fulminant liver failure and coma, two patients had reduced size livers because of large donor liver. There were no peroperative deaths. One of the elective patients died after three weeks from multiorgan failure and sepsis. Two of the emergency patients died after 20 and 22 days. One from graft dysfunction due to stenosis of the celiac trunk and the other of exudative pericarditis. One patient died from chronic rejection and CMV-infection after seven months. Complications were relatively few and acute rejection occurred in 40% of the patients. Fifteen patients are discharged with normal liver function and 11 of these were back at work, school or previous functions in the home. It is concluded that these results are comparable to the best results from other centres but that 21 transplants in 12 months must be a minimum activity.

Emergency liver transplantation is the treatment of choice in acute liver failure without signs of spontaneous regeneration. However, many patients rapidly contract irreversible neurological complications before transplantation can be performed. We used high-volume plasmapheresis to increase the time span to obtain a donor liver. Four patients with acute liver failure of unknown cause and a galactose elimination capacity indicative of a virtually extinct liver function were assigned maximum priority for liver transplantation. Plasmapheresis were performed daily until transplantation. Each time 8-10 liters of patient plasma were replaced with an equal volume of fresh donor plasma. There were no major complications. None of the patients developed irreversible neurological complications for 48-144 h at which time liver transplantation was performed. High volume plasmapheresis increases the time to obtain a donor liver for emergency liver transplantation and optimizes the condition for the surgical procedure.

From October 1990 to May 1992, nine of 38 patients with liver transplants (24%) had partial orthotopic liver transplantation on account of lack of size-matching donor livers. The preliminary results have presented very few problems; there was no per- or postoperative mortality and no surgical complications. Four patients had episodes of acute rejection which responded to anti-rejection therapy, and two patients were treated for CMV infection. All patients are discharged with normal liver function 4-9 weeks after transplantation (median 5 weeks). The method seems to be safe and can be used in centers with limited activity, where there is a problem of having the correct liver at the correct time.

In order to investigate hepatic clearance of vasoactive intestinal polypeptide we measured its concentration in blood from the common carotid artery, right atrium and portal vein during orthotopic liver transplantation in six pigs. Just after laparotomy we found a significantly higher concentration of vasoactive intestinal polypeptide in portal plasma compared to that of the right atrium (p less than 0.05). This difference was soon eliminated by a fall in portal concentration, and, apart from fluctuations in portal concentration, no significant gradient between portal and atrial blood was recorded during the remaining part of the operation. When portal concentrations exceeded 30 pmol/l, the median reduction after transhepatic passage was 29% (range 16.8%-63.9%), while portal concentrations less than 30 pmol/l had a median reduction of only 6.3% (range 1.4%-16.5%) (p less than 0.05). No gradient between right atrial and systemic arterial blood was recorded. We suggest that a concentration-dependent clearance of splanchnic vasoactive intestinal polypeptide takes place in the porcine liver.

Plasma glucose, insulin, and C-peptide were measured in seven pigs after intravenous bolus injection of 1 mg glucagon and injection of 15 g glucose on the 1st, 2nd, 4th, and 7th days after orthotopic liver transplantation. Fasting plasma glucose and the glycemic response to glucagon were lower at the first postoperative day than on any other day (P less than 0.05). Glucose clearance after injection of glucose was normal and without day-to-day variation. Plasma insulin and C-peptide concentrations were higher the first day after glucose stimulation (P less than 0.05), but no impairment of insulin secretion was found during the study. We conclude that, apart from low hepatic glucose production on the first postoperative day, glucose homeostasis was sufficient after liver transplantation.

The aminoterminal propeptide of type III collagen was monitored in serum during liver transplantation in nine pigs. The aim was to investigate whether removal of the liver causes any changes in the serum concentration of the propeptide. Another connective tissue component, hyaluronan, a glycosaminoglycan known to be degraded in the liver endothelial cells, was also measured. Removal of the liver caused a significant increase in the concentration of the intact propeptide as well as of hyaluronan. Gel filtration confirmed the increase in the amount of intact propeptide. However, another large propeptide-related antigen, eluted near the void volume, appeared in the antigen profile during the anhepatic phase. This peak probably represents the propeptide still attached to the collagen molecule (pN collagen). The findings indicate that the liver is involved in the degradation of the propeptide and of larger propeptide-holding proteins.

Hypotension and cardiac arrhythmia are commonly seen during liver transplantation both in man and in experimental animals. The cardiovascular changes may be explained by release of vasoactive substances, e.g. histamine, into the systemic circulation. Abdominal operations are followed by an increased histamine concentration in portal blood. If the liver clears excess histamine from the splanchnic system, an increased histamine concentration should not be found in the systemic circulation. We measured plasma histamine in peripheral arterial blood, blood from the right atrium and portal blood in different phase of liver transplantation in ten pigs. Histamine concentration increased in the portal vein in the anhepatic phase (basal 15.85 pmol/ml to 34.67 pmol/ml, median, p less than 0.05) but no changes were found in arterial or right atrium samples. Venous and later arterial revascularisation were not followed by any changes in histamine concentration in arteria and right atrium samples. We conclude that the transplanted liver can eliminate splanchnic histamine and that histamine is unlikely to be involved in the cardiovascular changes which are seen after revascularisation of the liver.