Abstract: Gene polymorphisms involved in hemostasis have been associated with an increased risk of thromboembolic events. The aim of this study was to assess whether prothrombotic gene polymorphism is a risk factor for hepatic vascular thrombosis after orthotopic liver transplantation (OLT).
Abstract: 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.
Abstract: Summary.  Background: Brain death is associated with a systemic inflammatory response resulting in diminished organ function in individuals transplanted with organs from brain dead donors. As inflammation is accompanied by activation of coagulation, we hypothesized that activation of hemostasis occurs in brain dead organ donors. Objectives: To assess the hemostatic status in brain dead organ donors. Patients and methods: In this study, we systematically assessed the hemostatic system in samples taken from 30 brain dead donors. As controls, blood samples from 30 living kidney donors were included. Results and conclusions: Compared with the living donors, brain dead donors showed significant platelet activation (assessed by glycocalicin plasma levels), and a profound dysbalance in the von Willebrand factor/ADAMTS13 axis, which is key in platelet attachment to damaged vasculature. Furthermore, compared with the living donors, brain dead donors showed a significantly increased activation of secondary hemostasis with formation of fibrin (assessed by plasma levels of prothrombin fragment 1 + 2, fibrinopeptide A and D-dimer). Finally, brain dead donors showed profound hypofibrinolysis as assessed by a global clot lysis assay, which was attributed to substantially elevated plasma levels of plasminogen activator inhibitor type 1. Collectively, our results show activation of hemostasis and dysregulated fibrinolysis in brain dead organ donors. This prothrombotic state may contribute to formation of microthrombi in transplantable organs, which potentially contributes to deterioration of organ function.
Abstract: Biliary complications, especially nonanastomotic biliary strictures (NAS), are a major cause of morbidity after orthotopic liver transplantation. Of all donor and recipient characteristics known to increase the risk of developing NAS, the role of prolonged ischemia times is most extensively described in the literature. However, there is increasing evidence that several other, non-ischemia-related factors play a critical role in the pathogenesis of NAS as well. The clinical presentation of NAS may vary considerably among liver transplant recipients, including large variations in time of occurrence, and in location and severity of the strictures. Additional underlying causes such as bile salt toxicity and immune-mediated injury are believed to explain the wide spectrum of biliary strictures after orthotopic liver transplantation. Current and emerging insight in the pathogenesis of NAS and potential targets to reduce biliary injury and preserve bile ducts are discussed in this overview.
Abstract: Background: Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). Matrix metalloproteinases (MMPs) are involved in connective tissue remodelling in chronic liver disease and complications after OLT. Aim: To evaluate the relationship between MMP-2 and MMP-9 gene polymorphisms and NAS. Methods: MMP-2 (-1306 C/T) and MMP-9 (-1562 C/T) gene promoter polymorphisms were analysed in 314 recipient-donor combinations. Serum levels of these MMPs were determined in subgroups of patients as well. NAS were identified with various radiological imaging studies performed within 4 years after OLT and defined as any stricture, dilation or irregularity of the intra- or extrahepatic bile ducts of the liver graft followed by an intervention, after exclusion of hepatic artery thrombosis and anastomotic strictures. Results: The average incidence of NAS was 15%. The major clinical risk factor for the development of NAS was PSC in the recipient. The presence of the MMP-2 CT genotype in donor and/or recipient was associated with a significantly higher incidence of NAS, up to 29% when both donor and recipient had the MMP-2 CT genotype (P=0.003). In the multivariate analyses, pre-OLT PSC (hazard ratio 2.1, P=0.02) and MMP-2 CT genotype (hazard ratio 3.5, P=0.003) were found to be independent risk factors for the development of NAS after OLT. No obvious association was found between NAS and the MMP-9 genotype and serum levels of the MMPs. Conclusion: MMP-2 CT genotype of donor and recipient is an independent risk factor, in addition to PSC, for the development of NAS after OLT.
Abstract: Hepatocellular carcinoma (HCC) arising in noncirrhotic and nonfibrotic liver (NC-HCC) is a rare type of malignancy frequently found in healthy young individuals. Partial liver resection is the treatment of choice with expected 5-year survival rates between 40% and 70%. As a result of absence of any symptom, a considerable number of patients are diagnosed when the malignancy has progressed to an advanced stage and the tumor has turned already unresectable. Some other patients suffer from intrahepatic recurrence after previous liver resection that cannot be re-resected or locally ablated. In these situations, liver transplantation (LT) may be the only potentially curative treatment. The indication for LT in NC-HCC patients, however, is not well established. The preliminary results of recent analysis of the European Liver Transplant Registry (ELTR) together with a literature review identified over 150 patients transplanted for NC-HCC during the last 15 years. In contrast to the historical data, these studies showed 5-year survival rates at 50-70% in well-selected patients. Important determinants of poor outcome are macrovascular invasion, lymph node involvement, and time interval of <12 months when LT is used as rescue therapy for intrahepatic recurrence after a previous partial liver resection. Interestingly, outcomes after both liver resection and LT for NC-HCC are much less influenced by tumor size than is the case with cirrhotic HCC. A large tumor size per se should, therefore, not to be seen as a strict contraindication for performing LT in patients with NC-HCC.
Abstract: The outcome of orthotopic liver transplantation (OLT) with controlled graft donation after cardiac death (DCD) is usually inferior to that with graft donation after brain death (DBD). This study compared outcomes from OLT with DBD versus controlled DCD donors with predefined restrictive acceptance criteria.
Abstract: Hepatitis E virus (HEV) infections are known to run a self-limiting course. Recently, chronic hepatitis E has been described in immunosuppressed patients after solid-organ transplantation. Besides the general recommendation to lower the immunosuppressive medication in these patients, there is currently no specific treatment. We here describe the successful use of pegylated interferon alpha-2b in the treatment of 2 liver transplant recipients who suffered a chronic HEV infection for 9 years (case A) or 9 months (case B). After 4 weeks of therapy, a 2-log decrease (case A) and a 3-log decrease (case B) in the viral load were observed. In case A, who received treatment for 1 year, serum viral RNA became undetectable from week 20 onward, and serum liver enzymes normalized completely. In case B, interferon was discontinued at week 16 because of a lack of a further decline in the viral load. However, 4 weeks after the cessation of therapy, viral RNA was no longer detectable in the serum, and this was probably related to a further decline in the immunosuppressive medication. Liver tests normalized completely. In both cases, no relapse has been noted so far. We conclude that pegylated interferon alpha-2b may be useful in the treatment of chronic HEV infections in patients in whom the reduction of the immunosuppressive medication alone is not sufficient.
Abstract: The Model for End-Stage Liver Disease (MELD) score is widely used to prioritize patients for liver transplantation. One of the pitfalls of the MELD score is the interlaboratory variability in all three components of the score (INR, bilirubin, creatinine). The interlaboratory variability in the INR has the largest impact on the MELD score, with a mean difference of around 5 MELD points in most studies. During the 3rd conference on Coagulopathy and Liver disease, a multidisciplinary group of scientists and physicians discussed possible solutions for the INR problem in the MELD score with the intention to provide a constructive contribution to the international debate on this issue. Here we will discuss possible solutions and highlight advantages and disadvantages.
Abstract: To evaluate whether a low postoperative platelet count is associated with a poor recovery of liver function in patients after partial liver resection.
Abstract: The vitamin D receptor (VDR) regulates the expression of drug metabolizing enzymes and transporters in intestine and liver, but the regulation of VDR expression in intestine and liver is incompletely understood. We studied the regulation of VDR mRNA expression by ligands for VDR, farnesoid X receptor (FXR), glucocorticoid receptor (GR) and protein kinase C alpha (PKCalpha) in rat and human ileum and liver using precision-cut slices. 1,25(OH)(2)D(3) induced VDR expression in rat ileum and liver, and human ileum but not in liver. Chenodeoxycholic acid (CDCA), but not lithocholic acid (LCA) and GW4064 induced VDR mRNA expression in rat ileum and liver. The PKCalpha activator, phorbol-12-myristate-13-acetate (PMA) induced the expression of VDR in the rat liver, and the induction of VDR by 1,25(OH)(2)D(3) and CDCA was inhibited by the PKCalpha inhibitor, bisindolyl maleimide I (Bis I). These results show that the expression of VDR is likely to be regulated by PKC but not by FXR or VDR activation at least in the rat liver. The VDR mediated induction of its target genes CYP3A1 and CYP3A2 by 1,25(OH)(2)D(3) or LCA in the rat ileum was strongly reduced in the presence of CDCA despite the higher VDR expression. Thus, CDCA might potentiate the toxicity of LCA by inhibiting its metabolism.
Abstract: Patients with liver disease often show substantial changes in their hemostatic system, which may aggravate further during liver transplantation. Recently, thrombin generation in patients with stable disease was shown to be indistinguishable from controls provided thrombomodulin, the natural activator of the anticoagulant protein C system, was added to the plasma. These results indicated that the hemostatic balance is preserved in patients with liver disease, despite conventional coagulation tests suggest otherwise.
Abstract: Patients with liver disease frequently acquire a complex disorder of hemostasis secondary to their disease. Routine laboratory tests such as the prothrombin time and the platelet count are frequently abnormal and point to a hypocoagulable state. With more sophisticated laboratory tests it has been shown that patients with liver disease may be in hemostatic balance as a result of concomitant changes in both pro- and antihemostatic pathways. Clinically, this rebalanced hemostatic system is reflected by the large proportion of patients with liver disease who can undergo major surgery without any requirement for blood product transfusion. However, the hemostatic balance in the patient with liver disease is relatively unstable as evidenced by the occurrence of both bleeding and thrombotic complications in a significant proportion of patients. Although it is still common practice to prophylactically correct hemostatic abnormalities in patients with liver disease before invasive procedures by administration of blood products guided by the prothrombin time and platelet count, we believe that this policy is not evidence-based. In this article, we will provide arguments against the traditional concept that patients with liver failure have a hemostasis-related bleeding tendency. Consequences of these new insights for hemostatic management will be discussed.
Abstract: The effects of the secondary bile acid, lithocholic acid (LCA), a VDR, FXR and PXR ligand, on the regulation of bile acid metabolism (CYP3A isozymes), synthesis (CYP7A1), and transporter proteins (MRP3, MRP2, BSEP, NTCP) as well as nuclear receptors (FXR, PXR, LXRα, HNF1α, HNF4α and SHP) were studied in rat and human precision-cut intestine and liver slices at the mRNA level. Changes due to 5 to 10μM of LCA were compared to those of other prototype ligands for VDR, FXR, PXR and GR. LCA induced rCYP3A1 and rCYP3A9 in the rat jejunum, ileum and colon, rCYP3A2 only in the ileum, rCYP3A9 expression in the liver, and CYP3A4 in the human ileum but not in liver. LCA induced the expression of rMRP2 in the colon but not in the jejunum and ileum but did not affect rMRP3 expression along the length of the rat intestine. In human ileum slices, LCA induced hMRP3 and hMRP2 expression. In rat liver slices, LCA decreased rCYP7A1, rLXRα and rHNF4α expression, induced rSHP expression, but did not affect rBSEP or rNTCP expression; whereas in the human liver, a small but significant decrease was found for hHNF1α expression. These data suggests profound species differences in the effects of LCA on bile acid transport, synthesis and detoxification. An examination of the effects of prototype VDR, PXR, GR and FXR ligands showed that these pathways are all intact in precision cut slices and that LCA exerted VDR, PXR and FXR effects. The LCA-induced altered enzymes and transporter expressions in the intestine and liver would affect the disposition of drugs.
Abstract: Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10(-16) and P = 4.1 × 10(-8), respectively).
Abstract: Background: The role of the immune system in the pathogenesis of nonanastomotic biliary strictures (NAS) after orthotopic liver transplantation (OLT) is unclear. A loss-of-function mutation in the CC chemokine receptor 5 (CCR5-Δ32) leads to changes in the immune system, including impaired chemotaxis of regulatory T cells. Aim: To investigate the impact of the CCR5-Δ32 mutation on the development of NAS. Methods: In 384 OLTs, we assessed the CCR5 genotype in donors and recipients and correlated this with the occurrence of NAS. Results: The CCR5-Δ32 allele was found in 65 (16.9%) recipients. The cumulative incidence of NAS at 5 years was 6.5% in wild-type (Wt) recipients vs 17.2% for carriers of the CCR5-Δ32 allele (P<0.01). In recipients with CCR5-Δ32, 50% of all NAS occurred >2 years after OLT, compared with 10% in the Wt group. In multivariate regression analysis, the adjusted risk of developing NAS was four-fold higher in recipients with CCR5-Δ32 (P<0.01). The highest risk of NAS was seen in patients transplanted for primary sclerosing cholangitis (PSC), who also carried CCR5-Δ32 (relative risk 5.4, 95% confidence interval 2.2-12.9; P<0.01). Donor CCR5 genotype had no impact on the occurrence of NAS. Conclusions: Patients with the CCR5-Δ32 mutation have a four-fold higher risk of developing NAS, compared with Wt recipients. This risk is even higher in patients with CCR5-Δ32 transplanted for PSC. Late development of NAS is significantly more present in patients with CCR5-Δ32. These data suggest that the immune system plays a critical role in the development of NAS after OLT.
Abstract: Acute liver failure and acute pancreatitis are accompanied by substantial changes in the hemostatic system. In acute liver failure, defective synthesis of coagulation factors and intravascular activation of coagulation results in thrombocytopenia and reduced levels of proteins involved in coagulation and fibrinolysis. Acute pancreatitis may be accompanied by intravascular activation of hemostasis mediated by inflammation and exposure of pancreatic tissue factor to the bloodstream. In animal models for both diseases, activation of hemostasis appears to contribute to the progression of the disease. Consequently, the use of anticoagulants may, in theory, be beneficial in humans. In practice, however, clinical use of anticoagulants in these patients is likely hampered by a substantial bleeding risk.
Abstract: Plasma levels of coagulation factors differ profoundly between adults and children, but are remarkably stable throughout adulthood. It is unknown which factors determine plasma levels of coagulation factors in a given individual. We hypothesized that the liver, which synthesizes coagulation factors, also controls plasma levels. We measured a panel of coagulation factors in samples taken from either adults or young children that underwent a liver transplantation using adult donor livers. Samples were taken 1-3 months after transplantation when the patients were clinically stable with adequate graft function. Following liver transplantation, the hemostatic profile of the pediatric group was remarkably different from that of the adult group, and resembled the hemostatic profile of normal children. Thus, children transplanted with an adult liver graft maintain a pediatric hemostatic profile following transplantation despite receiving an adult liver graft. These findings suggest that plasma levels of hemostatic proteins are not controlled by the liver.
Abstract: Infectious complications after orthotopic liver transplantation (OLT) are a major clinical problem. The lectin pathway of complement activation is liver-derived and a crucial effector of the innate immune defense against pathogens. Polymorphisms in lectin pathway genes determine their functional activity. We assessed the relationship between these polymorphic genes and clinically significant bacterial infections, i.e., sepsis, pneumonia, and intra-abdominal infection, and mortality within the first year after OLT, in relation to major risk factors in two cohorts from different transplant centers. Single-nucleotide polymorphisms in the mannose-binding lectin gene (MBL2), the ficolin-2 gene (FCN2), and the MBL-associated serine protease gene (MASP2) of recipients and donors were determined. Recipients receiving a donor liver in the principal cohort with polymorphisms in all three components i.e., MBL2 (XA/O; O/O), FCN2+6359T, and MASP2+371A, had a cumulative risk of an infection of 75% as compared to 18% with wild-type donor livers (P = 0.002), an observation confirmed in the second cohort (P = 0.04). In addition, a genetic (mis)match between donor and recipient conferred a two-fold higher infection risk for each separate gene. Multivariate Cox analysis revealed a stepwise increase in infection risk with the lectin pathway gene profile of the donor (hazard ratio = 4.52; P = 8.1 x 10(-6)) and the donor-recipient (mis)match genotype (hazard ratio = 6.41; P = 1.9 x 10(-7)), independent from the other risk factors sex and antibiotic prophylaxis (hazard ratio > 1.7 and P < 0.02). Moreover, patients with a lectin pathway gene polymorphism and infection had a six-fold higher mortality (P = 0.9 x 10(-8)), of which 80% was infection-related. CONCLUSION: Donor and recipient gene polymorphisms in the lectin complement pathway are major determinants of the risk of clinically significant bacterial infection and mortality after OLT.
Abstract: Platelets play a pivotal role in thrombosis and hemostasis, but an increasing variety of extra-hemostatic functions of platelets are being recognized. This review summarizes recent advances in the understanding of the role of platelets in various pathologies involving the liver. In ischemia/reperfusion injury of the liver, platelets appear to play a dual role. On one hand, platelets bind to the activated sinusoidal endothelium and induce apoptosis of these cells; on the other hand, platelet-derived serotonin assists in repair of the ischemic tissue. Furthermore, platelets are attracted to the liver following systemic inflammatory stimuli, but the significance of this finding is still unclear. Platelets and platelet-derived serotonin appear vital for liver regeneration following a partial liver resection. Finally, platelets and platelet-derived serotonin aggravate viral hepatitis by affecting the microcirculation in the liver.
Abstract: Patients with chronic or acute liver failure frequently show profound abnormalities in their hemostatic system. Whereas routine laboratory tests of hemostasis suggest these hemostatic alterations result in a bleeding diathesis, accumulating evidence from both clinical and laboratory studies suggest that the situation is more complex. The average patient with liver failure may be in hemostatic balance despite prolonged routine coagulation tests, since both pro- and antihemostatic factors are affected, the latter of which are not well reflected in routine coagulation testing. However, this balance may easily tip towards a hypo- or hypercoagulable situation. Indeed, patients with liver disease may encounter both hemostasis-related bleeding episodes as well as thrombotic events. During the 3rd International Symposium on Coagulopathy and Liver disease, held in Groningen, The Netherlands (18-19 September 2009), a multidisciplinary panel of experts critically reviewed the current data concerning pathophysiology and clinical consequences of hemostatic disorders in patients with liver disease. Highlights of this symposium are summarized in this review.
Abstract: Hepatic artery thrombosis (HAT) after pediatric orthotopic liver transplantation (OLT) is a serious complication resulting in bile duct necrosis and often requiring retransplantation. Immediate surgical thrombectomy/thrombolysis has been reported to be a potentially successful treatment for restoring blood flow and avoiding urgent retransplantation. The long-term results of this strategy remain to be determined. In 232 pediatric liver transplants, we analyzed long-term outcomes after urgent revascularization for early HAT. HAT developed in 32 patients (13.7%). In 16 children (50%), immediate surgical thrombectomy was performed in an attempt to salvage the graft. Fourteen patients (44%) underwent urgent retransplantation, and 2 (6%) died before further intervention. Immediate thrombectomy resulted in long-term restoration of the hepatic artery flow in 6 of 16 patients (38%) and in 1- and 5-year graft and patient survival rates of 83% and 67%, respectively. In 10 patients, revascularization was unsuccessful, and retransplantation was inevitable. The 1- and 5-year patient survival rates in this group decreased to 50% and 40%, respectively. After immediate retransplantation, the 5-year patient survival rate was 71%. In conclusion, immediate surgical thrombectomy for HAT after pediatric OLT results in long-term graft salvage in about one-third of patients. However, when thrombectomy is unsuccessful, long-term patient survival is lower than the survival of patients who underwent immediate retransplantation.
Abstract: Platelet transfusions have been identified as an independent risk factor for survival after orthotopic liver transplantation (OLT). In this study, we analyzed the specific causes of mortality and graft loss in relation to platelet transfusions during OLT.
Abstract: Long-term morbidity and survival after orthotopic liver transplantation (OLT) are to a large degree determined by cardiovascular disease and cancer. Tobacco use is a well-known risk factor for both. The aim of this study was to examine smoking behavior before and after OLT and to define groups at risk for resuming tobacco use after OLT. In addition, we looked for a relation between smoking and morbidity after OLT. All 401 adult patients with a follow-up of at least 2 years after OLT were included. Data were collected from the charts. A questionnaire about smoking habits at 4 time points before and after OLT was sent to all 326 patients alive, and 301 (92%) patients responded. Both before and after OLT, 53% of patients never used tobacco, and around 17% were active smokers. Of the active smokers during the evaluation for OLT, almost one-third succeeded in cessation, often during the waiting time for OLT. Twelve percent of former smokers restarted smoking, mainly after OLT. Tobacco use was the highest in patients with alcoholic liver disease (52% were active smokers before OLT, and 44% were after OLT) and the lowest in patients with primary sclerosing cholangitis (1.4% were active smokers before OLT). At 10 years, the cumulative rate of malignancies was 12.7% in active smokers versus 2.1% in nonsmokers (P = 0.019). No effect on skin cancer or cardiovascular disease was found. In conclusion, smoking is a serious problem after OLT and increases the risk for malignancy. Prevention programs should focus not only on active smokers but also on former smokers.
Abstract: Paediatric blunt hepatic trauma treatment is changing from operative treatment (OT) to non-operative treatment (NOT). In 2000 the American Pediatric Surgical Association has published guidelines for NOT of these injuries. Little is known about the treatment of paediatric liver trauma in the Netherlands.
Abstract: Patients with liver disease show profound changes in their hemostatic system, which may further change during liver transplantation. We previously demonstrated that highly elevated levels of the platelet adhesive protein von Willebrand factor (VWF) in patients with cirrhosis lead to an increased VWF-dependent platelet deposition under flow as compared to healthy controls. In this study we examined VWF parameters during the course of liver transplantation. We collected serial plasma samples from 20 patients undergoing liver transplantation in which we determined plasma levels of VWF and the VWF-cleaving protease ADAMTS13. Furthermore, we performed functional tests of VWF-dependent platelet adhesion. We found persistently elevated levels of VWF during and after liver transplantation. The capacity of VWF to interact with platelets normalized during the course of transplantation, and flow-mediated VWF-dependent platelet adhesion remained at levels far exceeding those observed in healthy individuals during and after transplantation. Plasma levels of ADAMTS13 dropped during transplantation, and in four patients levels below 10% of normal were observed after reperfusion. We observed the development of a hyperreactive primary hemostatic system, as evidenced by high levels of fully functional VWF and a temporary ADAMTS13 deficiency, during liver transplantation, and speculate that these changes contribute to postoperative thrombotic complications.
Abstract: Carcinoid tumours are rare, slow growing tumours, originating from cells of the neuroendocrine system. Staging of the disease is of paramount importance to determine the optimal treatment strategy but is notoriously difficult. A case of a 45-year-old male who presented with abdominal pain and flushes is presented. An abdominal computerised tomography-scan was performed which showed a solitary liver lesion, consisting of neuroendocrine tumour cells. Further staging with (18)F-DOPA PET, capsule endoscopy and double balloon enteroscopy revealed the localisation of the primary tumours in the small bowel, and the patient subsequently underwent surgery. The recent introduction of (18)F-DOPA PET, capsule endoscopy and double balloon enteroscopy in the diagnosis and staging of carcinoid tumours has made significant contributions to the management of this disease.
Abstract: Partial external biliary diversion (PEBD) is a promising treatment for children with progressive familial intrahepatic cholestasis (PFIC) and Alagille disease. Little is known about long-term outcomes.
Abstract: Nonanastomotic biliary strictures are troublesome complications after liver transplantation. The pathogenesis of NAS is not completely clear, but experimental studies suggest that bile salt toxicity is involved.
Abstract: Patients who have liver disease commonly present with alterations in platelet number and function. Recent data have questioned the contribution of these changes to bleeding complications in these patients. Modern tests of platelet function revealed compensatory mechanisms for the decreased platelet number and function, the most prominent compensatory mechanism being substantially elevated levels of the adhesive protein von Willebrand's factor. Consequently, standard diagnostic tests of platelet functions seem to be of little use to predict bleeding complication in patients who have liver disease. This article outlines the role of platelet abnormalities and possibilities for platelet function testing in patients who have liver disease.
Abstract: Intraoperative blood loss and transfusion of blood products are negatively associated with postoperative outcome after liver surgery. Blood loss can be minimized by surgical methods, including vascular clamping techniques, the use of dissection devices, and the use of topical hemostatic agents. Preoperative correction of coagulation tests with blood products has not been shown to reduce intraoperative bleeding and it may, in fact, enhance the bleeding risk. Maintaining a low central venous pressure has been shown to be effective in reducing blood loss during partial liver resections, and volume contraction rather than prophylactic transfusion blood products seems justified in patients undergoing major liver surgery. Although antifibrinolytic drugs have proved to be effective in reducing blood loss during liver transplantation, systemic hemostatic drugs are of limited value in reducing blood loss in patients undergoing partial liver resections.
Abstract: In this study, we compared the regulation of CYP3A isozymes by the vitamin D receptor (VDR) ligand 1 alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) against ligands of the pregnane X receptor (PXR), the glucocorticoid receptor (GR) and the farnesoid X receptor (FXR) in precision-cut tissue slices of the rat jejunum, ileum, colon and liver, and human ileum and liver. In the rat, 1,25(OH)(2)D(3) strongly induced CYP3A1 mRNA, quantified by qRT-PCR, along the entire length of the intestine, induced CYP3A2 only in ileum but had no effect on CYP3A9. In contrast, the PXR/GR ligand, dexamethasone (DEX), the PXR ligand, pregnenolone-16 alpha carbonitrile (PCN), and the FXR ligand, chenodeoxycholic acid (CDCA), but not the GR ligand, budesonide (BUD), induced CYP3A1 only in the ileum, none of them influenced CYP3A2 expression, and PCN, DEX and BUD but not CDCA induced CYP3A9 in jejunum, ileum and colon. In rat liver, CYP3A1, CYP3A2 and CYP3A9 mRNA expression was unaffected by 1,25(OH)(2)D(3), whereas CDCA decreased the mRNA of all CYP3A isozymes; PCN induced CYP3A1 and CYP3A9, BUD induced CYP3A9, and DEX induced all three CYP3A isozymes. In human ileum and liver, 1,25(OH)(2)D(3) and DEX induced CYP3A4 expression, whereas CDCA induced CYP3A4 expression in liver only. In conclusion, the regulation of rat CYP3A isozymes by VDR, PXR, FXR and GR ligands differed for different segments of the rat and human intestine and liver, and the changes did not parallel expression levels of the nuclear receptors.
Abstract: Intermittent ischemia (INT) can improve liver function following inflow occlusion. The aim was to test whether the number of cycles of INT can be increased without impairing liver function.
Abstract: This study assesses the relation between the anhepatic phase duration and the outcome after liver transplantation. Of 645 patients who underwent transplantation between 1994 and 2006, 194 were recipients of consecutive adult primary piggyback liver transplants using heart-beating donors. The anhepatic phase was defined as the time from the physical removal of the liver from the recipient to recirculation of the graft. Other noted study variables were the cold and warm ischemia times, donor and recipient age, donor and recipient body mass index, perioperative red blood cell (RBC) transfusion, indication for transplantation, and Model for End-Stage Liver Disease score. The primary outcome parameter was graft dysfunction, which was defined as either primary nonfunction or initial poor function according to the Ploeg-Maring criteria. The median anhepatic phase was 71 minutes (37-321 minutes). Graft dysfunction occurred in 27 patients (14%). Logistic regression analysis showed an anhepatic phase over 100 minutes [odds ratio (OR), 4.28], a recipient body mass index over 25 kg/m(2) (OR, 3.21), and perioperative RBC transfusion (OR, 3.04) to be independently significant predictive factors for graft dysfunction. One-year patient survival in patients with graft dysfunction was 67% versus 92% in patients without graft dysfunction (P < 0.001). A direct relation between the anhepatic phase duration and patient survival could, however, not be established. In conclusion, this study shows that liver transplant patients with an anhepatic phase over 100 minutes have a higher incidence of graft dysfunction. Patients with graft dysfunction have significantly worse 1-year patient survival.
Abstract: Patients with liver disease frequently have substantial changes in their haemostatic system. This is reflected in abnormal test results on routine coagulation screening assays such as the prothrombin time (PT), activated thromboplastin time (APTT) and platelet count. Traditionally, attempts were made to correct abnormalities in the haemostatic system as measured by routine coagulation assays prior to invasive procedures by infusion of platelets or fresh frozen plasma (FFP). Recent laboratory and clinical data have indicated that the haemostatic reserve in cirrhotic patients is relatively well maintained although the coagulation screening assays suggest otherwise. Pre-procedural correction of coagulation tests with blood products may therefore not be necessary, and may even have harmful side-effects. In particular, fluid overload resulting in exacerbation of portal hypertension by infusion of blood products may in fact promote bleeding. In recent years, it has become clear that reduction of the central and portal venous pressure by fluid restriction and avoidance of blood product transfusion is a beneficial strategy in minimizing bleeding during liver surgery in cirrhotic patients. Some investigators have even taken this a step further and suggested pre-procedural phlebotomy in liver transplant recipients. The aim of this review is to provide an overview of recent studies and developments which have changed our understanding of the clinical relevance of abnormal coagulation tests in patients with cirrhosis, and which have contributed to a reduction in blood loss and transfusion requirements when liver surgery is needed in these patients.
Abstract: To design a multifactorial biological modulation approach targeting ischemia reperfusion injury to augment viability of porcine liver grafts from non-heart-beating donors (NHBD).
Abstract: The regulation of the OSTalpha and OSTbeta expression was studied in the rat jejunum, ileum, colon and liver and in human ileum and liver by ligands for the farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR) and glucocorticoid receptor (GR) using precision cut tissue slices. The gradient of protein and mRNA expression in segments of the intestine for rOSTalpha and rOSTbeta paralleled that of rASBT. OSTalpha and OSTbeta mRNA expression, quantified by qRT-PCR, in rat jejunum, ileum, colon and liver, and in human ileum and liver was positively regulated by FXR and GR ligands. In contrast, the VDR ligand, 1,25(OH)2D3 decreased the expression of rOSTalpha-rOSTbeta in rat intestine, but had no effect on human ileum, and rat and human liver slices. Lithocholic acid (LCA) decreased the expression of rOSTalpha and rOSTbeta in rat ileum but induced OSTalpha-OSTbeta expression in rat liver slices, and human ileum and liver slices. The PXR ligand, pregnenolone-16alpha carbonitrile (PCN) had no effect. This study suggest that, apart from FXR ligands, the OSTalpha and OSTbeta genes are also regulated by VDR and GR ligands and not by PXR ligands. This study show that VDR ligands exerted different effects on OSTalpha-OSTbeta in the rat and human intestine and liver compared with other nuclear receptors, FXR, PXR, and GR, pointing to species- and organ-specific differences in the regulation of OSTalpha-OSTbeta genes.
Abstract: Worldwide, partial liver resections are increasingly being performed for primary or secondary hepatic malignancies. There are various techniques to reduce blood loss during liver surgery. Several topical haemostatic agents have been developed to improve haemostasis of the resection surface and these agents are used more and more, even although the true effects remain unclear.
Abstract: Hepatitis E virus (HEV) infection is known to run a self-limited course. Recently, chronic hepatitis E has been described in several immunosuppressed patients after solid organ transplantation. The prevalence of HEV infection after transplantation, however, is unknown. We studied HEV parameters [HEV RNA, HEV immunoglobulin M (IgM), and HEV immunoglobulin G (IgG) by enzyme-linked immunosorbent assay and confirmatory immunoblotting] in a cohort of 285 adult liver transplant recipients. The most recent freeze-stored sera were investigated, and if they were positive, a retrospective analysis was performed. Samples from 274 patients (96.1%) tested negative for all HEV parameters. This included a patient described earlier as having experienced an episode of chronic HEV hepatitis in the past. One patient was found positive for HEV RNA without HEV antibodies. She presently suffers from chronic HEV hepatitis and has also been described before. Sera from 9 patients tested positive for HEV IgG without HEV IgM or HEV RNA. Six of these 9 patients (2.1% of the total) were found to have HEV IgG antibodies in retrospect related to an HEV infection at some time pre-transplant as they also tested positive in a pretransplant serum sample. One of these 9 patients suffered in retrospect from a chronic HEV infection with mild hepatitis between 2 and 5 years after liver transplantation on the basis of the course of HEV RNA, IgM, and IgG, aminotransferases, and liver histology. Overall, the prevalence of acquired HEV hepatitis after liver transplantation was 1% in this cohort. We conclude that liver transplant recipients have a risk for chronic HEV infection, but the prevalence is low.
Abstract: Aprotinin is an antifibrinolytic drug that reduces blood loss during orthotopic liver transplantation (OLT). Case reports have suggested that aprotinin may be associated with an increased risk of thromboembolic complications. Recent studies in cardiac surgery also have suggested a higher risk of renal failure and postoperative mortality. Despite these concerns, no large-scale safety assessment has been performed in OLT. In a retrospective observational study involving 1492 liver transplants, we studied the occurrence of postoperative thromboembolic or thrombotic events and mortality in patients who received aprotinin (n = 907) and patients who did not (n = 585). The overall incidence of hepatic artery thrombosis and central venous complications (pulmonary embolism or inferior vena cava thrombosis) was 3.2% and 0.9%, respectively. In propensity score-adjusted analyses (C-index = 0.79), aprotinin was not associated with an increased risk of hepatic artery thrombosis [odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.50-2.01, P = 0.86]. Although central venous complications were found more frequently in patients receiving aprotinin, the difference was not statistically significant (OR = 2.95, 95% CI = 0.54-16.23, P = 0.32). In addition, no significant differences were found in 1-year mortality (OR = 1.21, 95% CI = 0.86-1.71, P = 0.32). In conclusion, this study did not demonstrate an increased risk of thrombotic complications or mortality when aprotinin is used during OLT.
Abstract: In patients with liver disease alterations in the hemostatic system frequently occur. Although it was generally believed that these changes result in a bleeding tendency, laboratory models and clinical data have shown evidence for a rebalanced hemostasis in liver disease, as a result of a concomitant decrease in both pro- and antihemostatic systems. The rebalanced system presumably has much narrower margins as compared to healthy individuals and therefore can more easily turn to either a hypo- or hypercoagulable state. Bleeding does occur in patients with liver disease but this is frequently related to non-hematological factors, for example bleeding from ruptured esophageal varices. Further clinical data supporting the concept of rebalanced hemostasis include the lack of major blood loss in a great proportion of patients during liver transplantation and the fact that patients with liver disease are not fully protected from thromboembolic complications including venous thrombosis and thrombosis of the hepatic vessels. It is still common practice to prophylactically treat patients with liver disease prior to invasive procedures to prevent bleeding. Because of a lack of data supporting the effectiveness of this management and the proven side-effects of transfusion of blood products, we believe transfusion of blood products can and should be restricted. The most important thrombotic problem after liver transplantation is hepatic artery thrombosis, a potentially devastating complication. Since the bleeding tendency in patients with liver disease may not be primarily caused by a deranged hemostatic system, the restricted use of anticoagulant drugs in the post-transplant setting should be reconsidered.
Abstract: Platelet function is thought to deteriorate during liver transplantation as a result of platelet activation and proteolysis of platelet receptors by plasmin following reperfusion. However, this hypothesis has never been formally tested. Twenty patients undergoing a first or second liver transplant were included in the study. Blood samples were taken at standardized time points during transplantation and up to 10 days after transplantation. Platelet activation was assessed by detection of the activation markers P-selectin and activated integrin alphaIIbbeta3 with flow cytometry. Proteolytic cleavage of platelet receptors was assessed by flow cytometry measurement of the constitutively expressed platelet receptors glycoprotein Ibalpha and integrin alphaIIbbeta3. In addition, using enzyme-linked immunosorbent assay techniques, we measured plasma levels of platelet activation products beta-thromboglobulin and platelet factor 4 and plasma levels of cleaved fragments of glycoproteins Ibalpha and V. Flow cytometry analyses provided no evidence of substantial platelet activation during transplantation. In fact, the expression of activated integrin alphaIIbbeta3 decreased postoperatively; this indicated that platelets were in a slightly activated state prior to surgery. Plasma levels of beta-thromboglobulin and platelet factor 4 also substantially decreased after transplantation. In addition, no changes were observed in the constitutively expressed platelet receptors or in the plasma levels of platelet receptor fragments, and this indicated a lack of substantial receptor proteolysis. In conclusion, no evidence was found for significant activation of circulating blood platelets or the proteolysis of key platelet receptors during liver transplantation. These findings suggest that the platelet functional capacity does not decrease during liver transplantation. Liver Transpl 15:956-962, 2009. (c) 2009 AASLD.
Abstract: To investigate the hypothesis that during the development of biliary atresia, early changes in hepatobiliary transport are mainly related to the inflammatory process and lead to intrahepatic cholestasis and subsequent liver injury, livers from mice with rhesus rotavirus-induced biliary atresia were analyzed for mRNA expression of hepatobiliary transporters, nuclear receptors, and inflammatory cytokines. Seven days after inoculation, despite high bile acid concentrations in the liver, gene expression of canalicular and basolateral hepatobiliary transporters and their regulatory nuclear receptors was down-regulated with concomitant increase in gene expression of inflammatory cytokines and rise in serum unconjugated bilirubin. At 14 d, hepatobiliary transporters and nuclear receptors remained down-regulated although the inflammatory response subsided. The percentage of conjugated bilirubin started to increase as extrahepatic biliary obstruction occurred. At 18 d, expression of hepatobiliary transporters remained low, expression of nuclear receptors returned to normal, while expression of inflammatory cytokines decreased further. Moreover, histology demonstrated progressive inflammation, bile duct damage, ductular proliferation, and hepatocyte necrosis. In conclusion, intrahepatic cholestasis due to inflammation-related down-regulation of basolateral and canalicular hepatobiliary transporters is an early event in the development of biliary atresia. Intrahepatic cholestasis contributes to the development of jaundice and liver injury.
Abstract: Biliary reconstruction using Roux-en-Y choledochojejunostomy has been suggested as a risk factor for the development of nonanastomotic biliary strictures (NAS) after liver transplantation. Roux-en-Y reconstruction, however, is preferentially used in patients transplanted for primary sclerosing cholangitis (PSC), and the disease itself is also associated with a higher incidence of NAS. The aim of this study was to determine whether Roux-en-Y reconstruction is really an independent risk factor for NAS. A series of 486 consecutive adult liver transplants were studied. Biliary reconstruction in patients transplanted for PSC was either by Roux-en-Y choledochojejunostomy or by duct-to-duct anastomosis, depending on the quality of the recipient's extrahepatic bile duct. Univariate and multivariate statistical analyses were used to identify risk factors for the development of NAS. The overall incidence of NAS was 16.5% (80/486). In univariate analyses, the following variables were significantly associated with NAS: PSC as the indication for transplantation, type of biliary reconstruction (Roux-en-Y versus duct-to-duct), and postoperative cytomegalovirus infection. After multivariate logistic regression analysis, PSC as the indication for transplantation (odds ratio, 2.813; 95% confidence interval, 1.624-4.875; P < 0.001) and postoperative cytomegalovirus infection (odds ratio, 2.098; 95% confidence interval, 1.266-3.477; P = 0.004) remained as independent risk factors for NAS. Biliary reconstruction using Roux-en-Y choledochojejunostomy was not identified as an independent risk factor for NAS. In conclusion, the association between Roux-en-Y choledochojejunostomy and NAS observed in previous studies can be explained by the more frequent use of Roux-en-Y reconstruction in patients with PSC. Roux-en-Y reconstruction itself is not an independent risk factor for NAS. Liver Transpl 15:924-930, 2009. (c) 2009 AASLD.
Abstract: Hepatitis E virus (HEV) infection is known to run a self-limiting course. Sporadic cases of acute hepatitis due to infection with HEV genotype 3, present in pig populations, are increasingly recognized. Zoonotic transmission seems infrequent. The entity of unexplained chronic hepatitis after liver transplantation has been recognized. Detection of HEV in 2 liver transplant recipients triggered a review of these cases. Freeze-stored sera were available for retrospective analysis. HEV antibodies were determined. For virus detection and identification, a fragment of the gene encoding the major capsid protein (open reading frame 2) was amplified by reverse-transcription polymerase chain reaction and sequenced to identify the genotype. Two months after liver transplantation, case A developed unexplained chronic hepatitis, which developed into cirrhosis. Retransplantation followed 7 years later, after which chronic hepatitis recurred. In retrospect, HEV RNA was present in serum 3 weeks after the first transplantation and remained present afterwards. HEV RNA was also present in retransplant liver tissue. HEV antibodies appeared late after retransplantation. Case B developed unexplained chronic hepatitis 7 years after transplantation. Retransplantation was needed 5 years later, after which no signs of hepatitis recurred. In retrospect, the period of chronic hepatitis up to the retransplantation coincided with HEV RNA in serum. In case B, antibodies developed, the viral load was much lower than in case A, and the virus seemed to be cleared after retransplantation. Genotyping in both cases revealed 2 unique strains of genotype 3. In conclusion, chronic HEV infection may develop in immunosuppressed patients, who may then serve as long-term carriers of the virus. We hypothesize that HEV may be the cause of chronic hepatitis in liver transplant recipients.
Abstract: Systemic haemostatic agents play an important role in the management of blood loss during major surgery where significant blood loss is likely and their use has increased in recent times as a consequence of demand for blood products outstripping supply and the risks associated with transfusions. Their main application is as prophylaxis to reduce bleeding in major surgery, including cardiac and orthopaedic surgery and orthotopic liver transplantation. Aprotinin has been the predominant agent used in this setting; of the other antifibrinolytic agents that have been studied, tranexamic acid is the most effective and epsilon-aminocaproic acid may also have a role. Eptacog alfa (recombinant factor VIIa) has also shown promise. Tranexamic acid, epsilon-aminocaproic acid and eptacog alfa are generally well tolerated; however, when considering the methods to reduce or prevent blood loss intra- and postoperatively, the benefits of these agents need to be weighed against the risk of adverse events. Recently, concerns have been raised about the safety of aprotinin after an association between increased renal dysfunction and mortality was shown in retrospective observational studies and an increase in all-cause mortality with aprotinin relative to tranexamic acid or epsilon-aminocaproic acid was seen after a pre-planned periodic analysis of the large BART (Blood conservation using Antifibrinolytics in a Randomized Trial) study. The latter finding resulted in the trial being halted, and aprotinin has subsequently been withdrawn from the market pending detailed analysis of efficacy and safety results from the study. Part 1 of this benefit-risk review examines the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in surgery, and provides individual benefit-risk profiles that may assist clinicians in selecting appropriate pharmacological therapy in this setting.
Abstract: The first part of this benefit-risk review examined the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in major surgery. The second part of this review examines the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in the treatment of excessive or heavy menstrual bleeding, and provides individual benefit-risk profiles that may assist clinicians in selecting appropriate pharmacological therapy in this setting. Historically, surgery has played a dominant role in treatment; however, pharmacological therapy is increasingly popular, especially in women who wish to retain their fertility. When selecting the appropriate treatment, patient preference should be considered, as well as the benefits and risks associated with each agent. Recommended pharmacological therapies that are effective and generally well tolerated include the levonorgestrel-releasing intrauterine system and the oral agents tranexamic acid, NSAIDs (e.g. mefenamic acid) and combined estrogen/progestogen oral contraceptives. In patients with an underlying bleeding disorder (e.g. von Willebrand disease), an additional option is intranasal desmopressin.
Abstract: Heme oxygenase-1 (HO-1) has been suggested as a cytoprotective gene during liver transplantation. Inducibility of HO-1 is modulated by a (GT)(n) polymorphism and a single nucleotide polymorphism (SNP) A(-413)T in the promoter. Both a short (GT)(n) allele and the A-allele have been associated with increased HO-1 promoter activity. In 308 liver transplantations, we assessed donor HO-1 genotype and correlated this with outcome variables. For (GT)(n) genotype, livers were divided into two classes: short alleles (<25 repeats; class S) and long alleles (> or =25 repeats; class L). In a subset, hepatic messenger ribonucleic acid (mRNA) expression was correlated with genotypes. Graft survival at 1 year was significantly better for A-allele genotype compared to TT-genotype (84% vs. 63%, p = 0.004). Graft loss due to primary dysfunction (PDF) occurred more frequently in TT-genotype compared to A-receivers (p = 0.03). Recipients of a liver with TT-genotype had significantly higher serum transaminases after transplantation and hepatic HO-1 mRNA levels were significantly lower compared to the A-allele livers (p = 0.03). No differences were found for any outcome variable between class S and LL-variant of the (GT)(n) polymorphism. Haplotype analysis confirmed dominance of the A(-413)T SNP over the (GT)(n) polymorphism. In conclusion, HO-1 genotype is associated with outcome after liver transplantation. These findings suggest that HO-1 mediates graft survival after liver transplantation.
Abstract: Bile duct injury after hepatic artery thrombosis (HAT) in liver transplantation is believed to be caused by ischemia predominantly. We aimed to define the involvement of bile secretory dysfunction in the pathogenesis of liver injury after HAT.
Abstract: Pulmonary embolism (PE) and intracardiac thrombosis (ICT) are rare but potentially lethal complications during orthotopic liver transplantation (OLT).
Abstract: Intraoperative transfusion of red blood cells (RBC) is associated with adverse outcome after orthotopic liver transplantation (OLT). Although experimental studies have shown that platelets contribute to reperfusion injury of the liver, the influence of allogeneic platelet transfusion on outcome has not been studied in detail. In this study, we evaluate the impact of various blood products on outcome after OLT.
Abstract: Between November 1982 and March 2006, 67 children with body weight < or =10 kg had a primary liver transplantation from deceased donors in our unit. The aim of this study was to analyze the outcome in terms of patient and graft survival and to search for factors affecting this outcome. Overall, one-, three-, five-, and 10-yr primary patient and graft survival rates were 73%, 71%, 66%, 63% and 59%, 56%, 53%, 48%, respectively. Twenty-four of 67 (36%) children died and in the remaining 22 (33%), the first grafts failed and they were retransplanted. Cox regression analysis revealed that a need for retransplantation and urgent transplantation were important predictors for patient survival (p = 0.04 and p = 0.001, respectively). To assess whether the need for retransplantation can be influenced, all study variables were compared between surviving grafts and failed grafts. Cox regression analysis showed that only donor/recipient (D/R) weight ratio proved to be independent predictor for graft survival (p = 0.004). After comparison of graft survival with the long rank test according to different D/R weight ratios (3.0-7.0), the cut-off point for significantly different graft survival approached 4.0. The one-, three-, five-, and 10-yr graft survival for technical variant grafts with a D/R weight ratio <4.0 was 85%, 68%, 68%, and 68% compared with a D/R weight ratio >4.0 was 44%, 38%, 38%, and 30%, respectively (p = 0.02). In summary, patient survival in children with body weight < or =10 kg is determined by urgent transplantation and the need for retransplantation. Graft loss and retransplantation in small children can be prevented by adequate size matching of donor and recipient whereby a D/R weight ratio <4.0 seems to offer the favorable outcome.
Abstract: Hemostatic alterations in cirrhosis involve molecular pathways that both promote and stabilize blood clotting and pathways that mediate clot dissolution. Orthotopic liver transplantation for end-stage liver disease historically was a long and risky procedure, accompanied by substantial blood loss. The aim of this review paper is to provide an overview of recent studies and developments that have gradually changed our understanding about the hemostatic system and changes that may occur in patients undergoing liver transplantation.
Abstract: Because of organ shortage and a constant imbalance between available organs and candidates for liver transplantation, expanded criteria donors are needed. Experience shows that there are wide variations in the definitions, selection criteria, and use of expanded criteria donors according to different geographic areas and different centers. Overall, selection criteria for donors have tended to be relaxed in recent years. Consensus recommendations are needed. This article reports the conclusions of a consensus meeting held in Paris in March 2007 with the contribution of experts from Europe, the United States, and Asia. Definitions of expanded criteria donors with respect to donor variables (including age, liver function tests, steatosis, infections, malignancies, and heart-beating versus non-heart-beating, among others) are proposed. It is emphasized that donor quality represents a continuum of risk rather than "good or bad." A distinction is made between donor factors that generate increased risk of graft failure and factors independent of graft function, such as transmissible infectious disease or donor-derived malignancy, that may preclude a good outcome. Updated data concerning the risks associated with different donor variables in different recipient populations are given. Recommendations on how to safely expand donor selection criteria are proposed.
Abstract: Apart from the well-known role of blood platelets in hemostasis, there is emerging evidence that platelets have various nonhemostatic properties that play a critical role in inflammation, angiogenesis, tissue repair and regeneration, and ischemia/reperfusion (I/R) injury. All these processes may be involved in the (patho)physiological alterations occurring in patients undergoing liver transplantation. Experimental and clinical research points toward a dualistic role of platelets in patients undergoing liver transplantation, resulting in both beneficial and detrimental effects. Although a low platelet count is generally considered a risk factor for perioperative bleeding, recent studies have indicated that platelet function in patients with cirrhosis may not be as abnormal as previously assumed. Platelet transfusions are frequently considered in liver transplant recipients to correct low platelet counts and to prevent bleeding; however, evidence-based transfusion thresholds are lacking, and the other detrimental and nonhemostatic properties of platelets are generally not weighed in this respect. First, platelets have been shown to contribute to I/R injury of the liver graft via induction of sinusoidal endothelial cell apoptosis. Second, platelet transfusion has been identified as an independent risk factor for reduced survival via mechanisms that are not completely understood yet. On the other hand, recent studies indicate that platelets are critically involved in restoration after liver injury and in liver regeneration via serotonin-mediated mechanisms. These findings make platelets both friend and foe in liver transplantation. The scientific challenge will be to further dissect the mechanisms and clinical relevance of these contrasting roles of platelets in liver transplantation.
Abstract: Intrahepatic bile duct strictures are a serious complication after non-heart-beating (NHB) liver transplantation. Bile salt toxicity has been identified as an important factor in the pathogenesis of bile duct injury and cholangiopathies. The role of bile salt toxicity in the development of biliary strictures after NHB liver transplantation is unclear.
Abstract: --Cholangiocarcinoma is a rare malignancy originating from the biliary epithelium. The disease can arise anywhere in the biliary tract: intrahepatic, perihilar or distal. The overall prognosis for cholangiocarcinoma is poor. --The treatment necessitates a multidisciplinary approach. --Radical resection of the extrahepatic bile ducts, usually in combination with concomitant partial liver resection, remains the only curative treatment. --Liver transplantation in combination with neoadjuvant chemoradiation therapy seems to be promising in a highly selected group of patients. --Palliative treatment should be targeted at adequate biliary drainage, preferably by stenting. --Radiotherapy and systemic chemotherapy are not standard treatment and should be applied in an experimental setting only. --New options such as photodynamic therapy and tyrosine kinase inhibitors are promising, but still experimental treatments.
Abstract: To study the impact of perineural growth as a prognostic factor in periampullary adenocarcinoma (pancreatic head, ampulla of Vater, distal bile duct, and duodenal carcinoma).
Abstract: Although several randomized controlled trials (RCTs) have shown the efficacy of antifibrinolytic drugs in liver transplantation, their use remains debated due to concern for thromboembolic complications. None of the reported RCTs has shown a higher incidence of these complications in treated patients; however, none of the individual studies has been large enough to elucidate this issue completely. We therefore performed a systematic review and meta-analysis of efficacy and safety endpoints in all published controlled clinical trials on the use of antifibrinolytic drugs in liver transplantation. Studies were included if antifibrinolytic drugs (epsilon-aminocaproic acid, tranexamic acid (TA) or aprotinin) were compared with each other or with controls/placebo. Intraoperative red blood cell and fresh frozen plasma requirements, the perioperative incidence of hepatic artery thrombosis, venous thromboembolic events and mortality were analyzed. We identified 23 studies with a total of 1407 patients which met the inclusion criteria. Aprotinin and TA both reduced transfusion requirements compared with controls. No increased risk for hepatic artery thrombosis, venous thromboembolic events or perioperative mortality was observed for any of the investigated drugs. This systematic review and meta-analysis does not provide evidence for an increased risk of thromboembolic events associated with antifibrinolytic drugs in liver transplantation.
Abstract: Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). The exact pathogenesis is unclear. Purpose of this study was to identify risk factors for the development of NAS after OLT. A total of 487 adult liver transplants with a median follow-up of 7.9 years were studied. All imaging studies of the biliary tree were reviewed. Cholangiography was routinely performed between postoperative days 10-14 and later on demand. Localization of NAS at first presentation was categorized into 4 anatomical zones of the biliary tree. Severity of NAS was semiquantified as mild, moderate, or severe. Donor, recipient, and surgical characteristics and variables were analyzed to identify risk factors for NAS. NAS developed in 81 livers (16.6%). Thirty-seven (7.3%) were graded as moderate to severe. In 85% of the cases, anatomical localization of NAS was around or below the bifurcation of the common bile duct. A large variation was observed in the time interval between OLT and first presentation of NAS (median 4.1 months; range 0.3-155 months). NAS presenting early (< or =1 year) after OLT were associated with preservation-related risk factors. Cold and warm ischemia times were significantly longer in patients with early NAS compared with NAS presenting late (>1 year) after OLT (694 minutes vs. 490 minutes, P = 0.01, and 57 minutes vs. 53 minutes, P < 0.05, respectively), and early NAS were more frequently located in the central bile ducts. NAS presenting late (>1 year) after OLT were found more frequently in the periphery of the liver and were more frequently associated with immunological factors, such as primary sclerosing cholangitis, as the indication for OLT (24% vs. 45%, P < 0.05). By separating cases of NAS on the basis of the time of presentation after transplantation, we were able to identify differences in risk factors, indicating different pathogenic mechanisms depending on the time of initial presentation.
Abstract: Nonanastomotic biliary strictures (NAS) after orthotopic liver transplantation (OLT) are associated with high retransplant rates. The aim of the present study was to describe the treatment of and identify risk factors for radiological progression of bile duct abnormalities, recurrent cholangitis, biliary cirrhosis, and retransplantation in patients with NAS. We retrospectively studied 81 cases of NAS. Strictures were classified according to severity and location. Management of strictures was recorded. Possible prognostic factors for bacterial cholangitis, radiological progression of strictures, development of severe fibrosis/cirrhosis, graft survival, and patient survival were evaluated. Median follow-up after OLT was 7.9 years. NAS were most prevalent in the extrahepatic bile duct. Twenty-eight patients (35%) underwent some kind of interventional treatment, leading to a marked improvement in biochemistry. Progression of disease was noted in 68% of cases with radiological follow-up. Radiological progression was more prevalent in patients with early NAS and one or more episodes of bacterial cholangitis. Recurrent bacterial cholangitis (>3 episodes) was more prevalent in patients with a hepaticojejunostomy. Severe fibrosis or cirrhosis developed in 23 cases, especially in cases with biliary abnormalities in the periphery of the liver. Graft survival, but not patient survival, was influenced by the presence of NAS. Thirteen patients (16%) were retransplanted for NAS. In conclusion, especially patients with a hepaticojejunostomy, those with an early diagnosis of NAS, and those with NAS presenting at the level of the peripheral branches of the biliary tree, are at risk for progressive disease with severe outcome.
Abstract: Renal dysfunction is frequently seen after orthotopic liver transplantation (OLT). Aprotinin is an antifibrinolytic drug which reduces blood loss during OLT. Recent studies in cardiac surgery suggested a higher risk of postoperative renal complications when aprotinin is used. The impact of aprotinin on renal function after OLT, however, is unknown. In 1,043 adults undergoing OLT, we compared postoperative renal function in patients who received aprotinin (n = 653) or not (n = 390). Using propensity score stratification (C-index 0.82) and multivariate regression analysis, aprotinin was identified as a risk factor for severe renal dysfunction within the first week, defined as increase in serum creatinine by >or= 100% (OR = 1.97, 95% CI = 1.14-3.39; p = 0.02). No differences in renal function were noted at 30 and 365 days postoperatively. Moreover, no significant differences were found in the need for renal replacement therapy (OR = 1.52, 95% CI = 0.94-2.46; p = 0.11) or in 1-year patient survival rate (OR = 1.14, 95% CI = 0.73-1.77; p = 0.64) in patients who received aprotinin or not. In conclusion, aprotinin is associated with a higher risk of transient renal dysfunction in the first week after OLT, but not with a higher need for postoperative renal replacement therapy or an increased risk of mortality.
Abstract: Liver transplantation has been an accepted treatment for end-stage liver disease since the 1980s. Currently it is a highly successful treatment for this indication. The aim of this review is to give a general update on recent developments in the field of liver transplantation. In the last decades considerable progress has been made in the care of liver transplant candidates and recipients. At present the one- and five-year patient survival rates are approximately 85 and 75%. The indications for liver transplantation are shifting and the number of absolute contraindications is decreasing. In the coming years, an increase in the number of transplant candidates can be expected. An important problem is the shortage of donor organs, for which many solutions are being explored. A recently introduced method for recipient selection is the MELD score using simple laboratory measurements. Perioperative care at the present time is characterised by a high degree of standardisation and rapidly declining blood loss during transplantation. Long-term care includes awareness and management of recurrent disease. Important causes of morbidity and mortality such as de novo malignancies and cardiovascular disease should be adequately screened for and managed. With the increasing success of liver transplantation, physicians should aim at reaching a normal life expectancy and quality of life for transplant recipients.
Abstract: Partial liver resections are the treatment of choice for patients with a malignant liver or bile duct tumor. The most frequent indications for partial liver resections are colorectal metastasis, hepatocellular carcinoma (HCC) and cholangiocarcinoma. Liver resection is the only therapy with a chance for cure in these patients. Refinements in surgical technique and increasing experience have contributed to a reduction in perioperative morbidity and mortality in recent years. Despite these improvements, partial liver resections remain a major surgical procedure and carry the risk for excessive blood loss and a subsequent need for blood transfusion. Blood transfusions have been associated with systemic side effects, such as depression of the immune system. Several studies have suggested that perioperative blood loss or transfusions have a negative impact on postoperative outcome. However, it has been debated whether this is due to a real cause-effect relationship or merely the result of more complicated surgery. We have reviewed the literature concerning studies focusing on the relationship between blood loss and blood transfusion during liver surgery for malignant tumors and postoperative outcome. Most studies were based on a retrospective analysis of single center experiences, using uni- and multivariate statistical methods. Most studies have demonstrated a significant and clinically relevant association between blood transfusion and postoperative mortality and morbidity, especially postoperative infectious complications. The effect of blood transfusions on tumor recurrence and more long-term mortality is much less clear and evidence varies depending on the type of malignancy. The strongest indication that blood transfusion may have an impact on tumor recurrence has been found for patients with early stages of HCC. However, overall, no such effect could be demonstrated for patients undergoing partial liver resection for late stages of HCC, colorectal liver metastasis or cholangiocarcinoma.
Abstract: The origin of blood loss during liver surgery is multifactorial. Surgical skill, technique, anesthesiological care, but also hyperfibrinolysis have been shown to play a role in the origin of bleeding during partial hepatectomy and liver transplantation. The latter has provided the scientific basis for the prophylactic use of antifibrinolytic drugs, such as aprotinin and nafamostat mesilate in liver surgery. Recently however, concern has been voiced about potential risks associated with aprotinin, including renal failure and thromboembolic events. In this review we discuss the efficacy and safety issues of aprotinin and nafamostat mesilate in liver surgery. We identified a total of 19 studies on the use of either aprotinin or nafamostat mesilate in liver surgery reported in the time period between 1966 and July 2006. The use of aprotinin or nafamostat mesilate in partial hepatectomies was studied in three studies. In 16 studies the use of aprotinin in liver transplantation was investigated. With respect to partial hepatectomy, improvements in surgical technique and anesthesiological care seem to be more important in reducing blood loss than the use of the antifibrinolytic drugs. Aprotinin may be indicated in a selected group of patients with cirrhosis undergoing liver resection, but further studies in this specific group of patients will be needed. In liver transplantation, the use of aprotinin is associated with a significant reduction in blood loss and transfusion requirements of around 30-40%. Results of prospective studies do not provide support for safety concerns as no increased risk for thromboembolic events or renal dysfunction has been observed in liver transplant patients treated with aprotinin. In conclusion, there is currently no scientific support for the routine use of aprotinin or nafamostat mesilate in patients undergoing partial hepatectomy, whereas the efficacy of aprotinin in liver transplantation is well established. More studies will be needed to address the safety aspects of aprotinin in patients undergoing liver surgery in more detail.
Abstract: Intestinal transplantation for intestinal failure is no longer an experimental procedure, but an accepted treatment for patients who fail total parenteral nutrition (TPN) therapy. Early referral for evaluation for small bowel transplantation has to be considered in patients with permanent intestinal failure who have occlusion of more than two major veins, frequent line-related septic episodes, impairment of liver function or an unacceptable quality of life. With the increased experience in post-transplant patient care and newer forms of induction (thymoglobulin, IL-2 receptor antagonists) and maintenance (tacrolimus) therapies the 1-year graft survival has increased to 65% for isolated and to 59% for liver/small bowel transplantation, and is further improving. Rejection, bacterial, fungal and viral (CMV, EBV) infection, post-transplant lymphoproliferative disease (PTLD) and graft versus host disease (GvHD) are the most common complications after intestinal transplantation. Although most of the long-term survivors are TPN-independent and have a good quality of life, the risk of the procedure and long-term adverse effects of immunosuppressive medication limits small bowel, or liver/small bowel transplantation only to patients with severe complications of TPN therapy.
Abstract: After liver transplantation, the prevalence of complications related to the biliary system is 6-35%. In recent years, the diagnosis and treatment of biliary problems has changed markedly. The two standard methods of biliary reconstruction in liver transplant recipients are the duct-to-duct choledochocholedochostomy and the Roux-en-Y-hepaticojejunostomy. Biliary leakage occurs in approximately 5-7% of transplant cases. Leakage from the site of anastomosis, the T-tube exit site and donor or recipient remnant cystic duct is well described. Symptomatic bile leakage should be treated by stenting of the duct by endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTCD). Biliary strictures can occur at the site of the anastomosis (anastomotic stricture; AS) or at other locations in the biliary tree (non-anastomotic strictures; NAS). AS occur in 5-10% of cases and are due to fibrotic healing. Treatment by ERCP or PTCD with dilatation and progressive stenting is successful in the majority of cases. NAS can occur in the context of a hepatic artery thrombosis, or with an open hepatic artery (ischaemic type biliary lesions or ITBL). The incidence is 5-10%. NAS has been associated with various types of injury, e.g. macrovascular, microvascular, immunological and cytotoxic injury by bile salts. Treatment can be attempted with multiple sessions of dilatation and stenting of stenotic areas by ERCP or PTCD. In cases of localized diseased and good graft function, biliary reconstructive surgery is useful. However, a significant number of patients will need a re-transplant. When biliary strictures or ischaemia of the graft are present, stones, casts and sludge can develop.
Abstract: In recent years, the hemostatic agent recombinant factor VIIa (rFVIIa) has emerged as a potentially new therapeutic agent for management of coagulopathy in patients with cirrhosis or following severe traumatic injury, a complex problem for clinicians in which standard treatment strategies are not always effective. As with other hemostatic agents, a primary safety concern of rFVIIa therapy is the theoretical possibility that systemic administration could confer an increased risk of thrombotic complications. So far, clinical experience indicates rFVIIa to be a safe treatment for currently approved indications within hemophilia. Little information is available, however, for patient populations outside this clinical setting.
Abstract: Authors analyzed the differences in the outcome of two European liver transplant centers differing in case volume and experience. The first was the Transplantation and Surgical Clinic, Semmelweis University, Budapest, Hungary (SEB) and the second the University Medical Center Groningen, Groningen, The Netherlands (UMCG). We investigated if such differences could be explained. The 1-, 3- and 5-year patient survival in the UMCG was 86%, 80%, and 77% compared with 65%, 56%, and 55% in SEB. Graft survival at the same time points was 79%, 71%, and 66% in the UMCG and 62%, 55%, and 53% in SEB. Significant differences were present regarding the donor and recipient age, diagnosis mix, disease severity and operation variables, per-operative transfusion rate, vascular complications, postoperative infection rate, and need for renal replacement. To determine factors correlating with survival, a separate uni- and multivariate analysis was performed in each center individually, between study parameters and patient survival. In both centers, peri-operative red blood cell (RBC) transfusion rate was a significant predictor for patient survival. The difference in blood loss can be explained by different operation techniques and shorter operation time in SEB, with consequently less time spent on hemostasis. It was jointly concluded that measures to reduce blood loss by adapting the operation technique might lead to improved survival and reduced morbidity.
Abstract: Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug resistance 2 Mdr2 gene (Mdr2+/-) were transplanted into wild-type recipient mice. Mdr2+/- mice secrete only 50% of the normal amount of phospholipids into their bile, leading to an abnormally high bile salt/phospholipid ratio. In contrast to homozygous Mdr2-/- mice, the Mdr2+/- mice have normal liver histology and function under normal conditions. Two weeks after OLT, bile duct injury and cholestasis were assessed by light and electron microscopy, as well as through molecular and biochemical markers. There were no signs of bile duct injury or intrahepatic cholestasis in liver grafts from wild-type donors. Liver grafts from Mdr2+/- donors, however, had enlarged portal tracts with cellular damage, ductular proliferation, biliostasis, and a dense inflammatory infiltrate after OLT. Parallel to this observation, recipients of Mdr2+/- livers had significantly higher serum transaminases, alkaline phosphatase, total bilirubin, and bile salt levels, as compared with recipients of wild-type livers. In addition, hepatic bile transporter expression was compatible with the biochemical and histological cholestatic profile found in Mdr2+/- grafts after OLT. In conclusion, toxic bile composition, due to a high biliary bile salt/phospholipid ratio, acted synergistically with cold ischemia in the pathogenesis of bile duct injury after transplantation.
Abstract: We retrospectively studied the prevalence, presentation, results of treatment, and graft and patient survival of grafts developing an anastomotic biliary stricture (AS) in 531 adult liver transplantations performed between 1979 and 2003. Clinical and laboratory information was obtained from the hospital files, and radiological studies were re-evaluated. Twenty-one possible risk factors for the development of AS (variables of donor, recipient, surgical procedure, and postoperative course) were analyzed in a univariate and stepwise multivariate model. Forty-seven grafts showed an anastomotic stricture: 42 in duct-to-duct anastomoses, and 5 in hepaticojejunal Roux-en-Y anastomoses. The cumulative risk of AS after 1, 5, and 10 years was 6.6%, 10.6%, and 12.3% respectively. Postoperative bile leakage (P = 0.001), a female donor/male recipient combination (P = 0.010), and the era of transplantation (P = 0.006) were independent risk factors for the development of an AS. In 47% of cases, additional (radiologically minor) nonanastomotic strictures were diagnosed. All patients were successfully treated by 1 or more treatment modalities. As primary treatment, endoscopic retrograde cholangiopancreaticography (ERCP) was successful in 24 of 36 (67%) cases and percutaneous transhepatic cholangiodrainage in 4 of 11 (36%). In the end 15 patients (32%) were operated, all with long-term success. AS presenting more than 6 months after transplantation needed more episodes of stenting by ERCP, and more stents per episode compared to those presenting within 6 months and recurred more often. Graft and patient survival were not impaired by AS.
Abstract: The exact frequency and clinical consequences of surgical hepatic injuries during organ procurement are unknown. We analyzed the incidence, risk factors, and clinical outcome of surgical injuries in 241 adult liver grafts. Hepatic injuries were categorized as parenchymal, vascular, or biliary. Outcome variables were bleeding complications, hepatic artery thrombosis (HAT), and graft survival. In 82 livers (34%), 96 injuries were detected. Most injuries were minor, but clinically relevant injuries were detected in 6.6% (16/241) of the livers. Fifty (21%) liver grafts had some degree of parenchymal or capsular injury, 40 (17%) had vascular injury, and 6 (2%) had an injury to the bile duct. Procurement region was the only risk factor significantly associated with surgical injury. The rate of hepatic artery injury was significantly higher in livers with aberrant arterial anatomy. Bleeding complications were found in 18% of patients who received livers with a parenchymal or capsular injury in contrast to 9% without parenchymal injury (P = 0.065). HAT was found in 23% of the patients who received a liver with arterial injury compared to 4% without arterial injury (P = 0.001). Overall graft survival rates were not significantly different for grafts with or without anatomical injury. In conclusion, surgical injuries of donor livers are an underestimated problem in liver transplantation and can be observed in about one-third of all cases. Clinically relevant injuries are detected in 6.6% of all liver grafts. Arterial injuries are associated with an increased risk of HAT.
Abstract: Biliary complications are a major source of morbidity, graft loss, and even mortality after liver transplantation. The most troublesome are the so-called ischemic-type biliary lesions (ITBL), with an incidence varying between 5% and 15%. ITBL is a radiological diagnosis, characterized by intrahepatic strictures and dilatations on a cholangiogram, in the absence of hepatic artery thrombosis. Several risk factors for ITBL have been identified, strongly suggesting a multifactorial origin. The main categories of risk factors for ITBL include ischemia-related injury; immunologically induced injury; and cytotoxic injury, induced by bile salts. However, in many cases no specific risk factor can be identified. Ischemia-related injury comprises prolonged ischemic times and disturbance in blood flow through the peribiliary vascular plexus. Immunological injury is assumed to be a risk factor based on the relationship of ITBL with ABO incompatibility, polymorphism in genes coding for chemokines, and pre-existing immunologically mediated diseases such as primary sclerosing cholangitis and autoimmune hepatitis. The clinical presentation of patients with ITBL is often not specific; symptoms may include fever, abdominal complaints, and increased cholestasis on liver function tests. Diagnosis is made by imaging studies of the bile ducts. Treatment starts with relieving the symptoms of cholestasis and dilatation by endoscopic retrograde cholangiopancreaticography (ERCP) or percutaneous transhepatic cholangiodrainage (PTCD), followed by stenting if possible. Eventually up to 50% of the patients with ITBL will require a retransplantation or may die. In selected patients, a retransplantation can be avoided or delayed by resection of the extra-hepatic bile ducts and construction of a hepaticojejunostomy. More research on the pathogenesis of ITBL is needed before more specific preventive or therapeutic strategies can be developed.
Abstract: Fever of unknown origin (FUO) frequently complicates the management of pediatric patients with terminal chronic liver failure during the pretransplantation period and may lead to increased morbidity and mortality. Nonhepatic origins of systemic infections may render the patient unsuitable for transplantation whereas infections within the liver may require organ resection for a cure. Therefore, accurate localization of the infection focus is critical for optimal management of children on the waiting list for liver transplantation. Here we report our experience using [18 F]fluordeoxyglucose (FDG)-positron emission tomography (PET) to detect the origin of infection in 11 children with biliary cirrhosis presenting with FUO during the waiting period for liver transplantation. In 5 children, positive intrahepatic FDG-PET signals correlated with bacterial cultures of the excised liver and/or anatomic or histologic signs of infection. Based on the FDG-PET findings, these patients underwent transplantation after continuous antibiotic treatment with ongoing, recurrent episodes of fever. In 6 children, no abnormal hepatic FDG-PET signals were found and no infections could be detected in the liver. Transplantation in these patients was performed only after becoming afebrile. Standard imaging techniques did not reveal abnormalities compatible with infection in any of the children. In conclusion, in children with biliary cirrhosis and FUO on the waiting list for liver transplantation, information obtained by FDG-PET imaging may be useful for decisions on therapy and suitability for liver transplantation.
Abstract: OBJECTIVE. To describe the experience with combined liver and kidney transplantation at the University Medical Centre Groningen, The Netherlands. DESIGN. Retrospective.
Abstract: Upregulation of heme oxygenase-1 (HO-1) has been proposed as a critical mechanism protecting against cellular stress during liver transplantation, providing a potential target for new therapeutic interventions. We investigated the feasibility of in vivo bioluminescence imaging (BLI) to noninvasively quantify the spatiotemporal expression of HO-1 after warm hepatic ischemia in living animals. Luciferase activity was measured by BLI as an index of HO-1 transcription in transgenic reporter mice (Ho1-luc) at standardized time points after 60 minutes of warm hepatic ischemia. HO-1 mRNA levels were measured in postischemic livers of mice sacrificed at the same time points in separate experiments. Bioluminescent signals from postischemic liver lobes were first detected at 3 hours after reperfusion. Peak levels were reached at 9 hours, after which bioluminescent activity declined and returned to baseline values at 48 hours after reperfusion. Upregulation of HO-1 as detected by in vivo BLI was preceded by increased HO-1 mRNA expression and confirmed by enhanced immunohistochemical staining of hepatocytes. In conclusion, this study shows that in vivo BLI allows a sensitive assessment of HO-1 expression after hepatic ischemia in living animals. The capability of whole-body temporal imaging of HO-1 expression provides a valuable tool in the development of novel strategies to modulate HO-1 expression in liver transplantation.
Abstract: The purpose of this study was to investigate whether differences existed in demography and outcome after resection for hepatocellular carcinoma (HCC) in patients with a normal liver compared to patients with a diseased liver.
Abstract: No consensus exists regarding the optimal reconstruction of the cavo-caval anastomosis in piggyback orthotopic liver transplantation (PB-LT). The aim of this study was to analyze our experience with end-to-side (ES) cavo-cavostomy. Outcome parameters were patient and graft survival and surgical complications. During the period 1995-2002 146 full-size PB-LT in 137 adult patients were performed with ES cavo-cavostomy without the routine use of temporary portocaval shunt (TPCS). In 12 patients (8%) this technique was used for implantation of second or third grafts. Veno-venous bypass was not used in any case and TPCS was performed only in eight patients (6%). One-, three- and five-yr patient and graft survival were 84%, 79% and 75%, and 81%, 74% and 69%, respectively. The median number of intraoperative transfusion of packed red blood cells (RBC) was 2.0 (range 0-33) and 30% of the patients (n = 43) did not require any RBC transfusion. Surgical complications of various types were observed after 49 LT (34%) and none of the complications was specifically related to the technique of ES cavo-cavostomy. Our experience indicates that PB-LT with ES cavo-cavostomy is a safe procedure, can safely be performed without the routine use of a TPCS, has a very low risk of venous outflow obstruction and can also be used effectively during retransplantations.
Abstract: Upregulation of heme oxygenase-1 (HO-1) has been proposed as an adaptive mechanism protecting against ischemia/reperfusion (I/R) injury. We investigated HO-1 expression in 38 human liver transplants and correlated this with I/R injury and graft function. Before transplantation, median HO-1 mRNA levels were 3.4-fold higher (range: 0.7-9.3) in donors than in normal controls. Based on the median value, livers were divided into two groups: low and high HO-1 expression. These groups had similar donor characteristics, donor serum transaminases, cold ischemia time, HSP-70 expression and the distribution of HO-1 promoter polymorphism. After reperfusion, HO-1 expression increased significantly further in the initial low HO-1 expression group, but not in the high HO-1 group. Postoperatively, serum transaminases were significantly lower and the bile salt secretion was higher in the initial low HO-1 group, compared to the high expression group. Immunofluorescence staining identified Kupffer cells as the main localization of HO-1. In conclusion, human livers with initial low HO-1 expression (<3.4 times controls) are able to induce HO-1 further during reperfusion and are associated with less injury and better function than initial high HO-1 expression (>3.4 times controls). These data suggest that an increase in HO-1 during transplantation is more protective than high HO-1 expression before transplantation.
Abstract: To correlate TP53 mutations with angiogenic status of the tumor and prognosis after liver surgery in patients with colorectal liver metastases and to correlate immunohistochemical staining of p53 protein with TP53 gene mutations.
Abstract: Small bowel transplantation for intestinal failure is no longer an experimental procedure, but an accepted treatment for patients where total parenteral nutrition (TPN) therapy for intestinal failure is unsuccessful. Early referral for screening for small bowel transplantation should be considered in patients with permanent intestinal failure who have occlusion of more than 2 major veins, frequent line-related septic episodes, impairment of liver function or an unacceptable quality of life. With the increased experience in post-transplant patient care and newer forms of induction (thymoglobulin, IL-2 receptor antagonists) and maintenance (tacrolimus) therapies, the 1-year graft survival has increased to 65% for isolated and to 59% for liver/small bowel transplantation and is further improving. Rejection, bacterial, fungal and viral (Cytomegalovirus, Epstein-Barr-virus) infections, post-transplant lymphoproliferative disease and graft versus host disease are the most common complications after intestinal transplantation. Although most of the long-term survivors are TPN-independent and have a good quality of life, the risk of the procedure and long-term adverse effects ofimmunosuppressive medication limits small bowel, or liver/small bowel transplantation only to patients with severe complications of TPN therapy.
Abstract: The aim of the study was to assess whether there is a difference in outcome after sequential or simultaneous revascularization during orthotopic liver transplantation (OLT) in terms of patient and graft survival, mortality, morbidity, and liver function. The study population consisted of 102 adult patients with primary full-size piggyback OLT transplanted between January 1998 and December 2001. In 71 patients (70%) the grafts were sequentially reperfused after completion of the portal vein anastomosis and subsequent arterial reconstruction was performed (sequential reperfusion [SeqR] group). In 31 patients (30%) the graft was reperfused simultaneously via the portal vein and hepatic artery (simultaneous reperfusion [SimR] group). Patient and graft survival at 1, 3, and 6 months and at 1 year did not differ between the SeqR group and the SimR group. The red blood cell (RBC) requirements were significantly higher in the SimR group (5.5 units; range 0-20) in comparison to the SeqR group (2 units; range 0-19) (P = 0.02). Apart from a higher number of biliary anastomotic complications and abdominal bleeding complications in the SimR group in comparison to the SeqR group (13% vs. 2% and 19% vs. 6%, respectively; P = 0.06), morbidity was not different between the groups. No differences between the groups were observed regarding the incidence of primary nonfunction (PNF), intensive care unit stay, and acute rejection. This was also true for the severity of rejections. Postoperative recuperation of liver function was not different between the groups. In conclusion, no advantage of either of the 2 reperfusion protocols could be observed in this analysis, especially with respect to the incidence of ischemic type biliary lesions (ITBL).
Abstract: Liver transplantation is the treatment of choice in selected patients with end-stage liver disease. Postoperative complications often require surgical re-intervention. This study is a retrospective single-centre study to assess the incidence and type of surgical re-intervention during the in-hospital period after liver transplantation and to identify predictors of this re-intervention. From 1994 to 2002, 231 consecutive adult liver transplantations were performed. Re-intervention was classified as biliary, vascular, bleeding, septicaemia, re-transplantation or as miscellaneous. One hundred and thirty-nine surgical re-interventions were performed in 79 of 231 patients (34%). Septicaemia (44%) and bleeding (27%) were the most frequent indications for re-intervention, followed by biliary (10%) re-intervention. Vascular re-intervention, re-transplantation, and re-intervention for miscellaneous reasons, were performed in 7% each. Of all analysed variables (gender, age, diagnosis, acute liver failure, Child-Pugh classification, Karnofsky score, previous abdominal surgery, creatinine clearance, prothrombin time, anti-thrombin, platelet count, surgical technique, cold ischaemia time, warm ischaemia time, functional anhepatic time, anatomic anhepatic time, revascularisation time, year of transplantation, aprotinin administration, transfused platelet concentrate, and red blood cell transfusion requirements), only the number of transfused red blood cell concentrates (RBCs) was identified as a predictor of surgical re-intervention. Median RBC transfusion requirement during liver transplantation was 2.9 l (range 0-18.8 l) in the re-intervention group compared with 1.5 l (range 0-13.4 l) in the non-re-intervention group (P<0.001). This study revealed intraoperative blood loss as the main determinant of early surgical re-intervention after liver transplantation and emphasises the need for further attempts to control blood loss during liver transplantation.
Abstract: The adenosine triphosphate (ATP)-binding cassette (ABC)-transporters ABCG5 and ABCG8 have been shown to mediate hepatic and intestinal excretion of cholesterol. In various (genetically modified) murine models, a strong relationship was found between hepatic expression of ABCG5/ABCG8 and biliary cholesterol content. Our study aimed to relate levels of hepatic expression of ABCG5 and ABCG8 to biliary excretion of cholesterol in man. From 24 patients who had received a liver transplant, bile samples were collected daily after transplantation over a 2-week period to determine biliary composition. Expression of ABCG5, ABCG8, MDR3, and BSEP was assessed by real-time polymerase chain reaction (PCR) in liver biopsy specimens collected before and after transplantation. Levels of hepatic ABCG5, ABCG8, and MDR3 messenger RNA (mRNA) were strongly correlated. After transplantation, the biliary secretion rate of cholesterol continuously increased, coinciding with gradual increases in bile salt and phospholipid secretion. In contrast, hepatic levels of ABCG5 and ABCG8 mRNA remained unchanged. Surprisingly, no correlation was found between the hepatic expression of ABCG5 and ABCG8 and rates of biliary cholesterol secretion, normalized for biliary phospholipid secretion. As expected, the concentration of biliary phospholipids correlated well with MDR3 expression. In conclusion, the strong relationship between ABCG5 and ABCG8 gene expression is consistent with the coordinate regulation of both genes, and in line with heterodimerization of both proteins into a functional transporter. Hepatic ABCG5/ABCG8 expression, at least during the early phase after transplantation, is not directly related to biliary cholesterol secretion in humans. This finding suggests the existence of alternative pathways for the hepatobiliary transport of cholesterol that are not controlled by ABCG5/ABCG8.
Abstract: Blood loss during liver transplantation has long been recognized as an important cause of morbidity and, especially in the early days, also mortality. It is well known that blood transfusions are associated with an increased risk of postoperative complications, such as infections, pulmonary complications, protracted recovery, and a higher rate of reoperations. Many studies have been performed during the past decades to elucidate the mechanisms of increased blood loss in liver transplantation. In the late 1980s, primary hyperfibrinolysis was identified as an important mechanism of bleeding during liver transplantation. This has provided the scientific basis for the use of antifibrinolytic drugs in liver transplant recipients. Several randomized, controlled studies have shown the efficacy of these compounds in reducing blood loss and transfusion requirements during liver transplantation. In addition, increasing experience and improvements in surgical technique, anesthesiological care and better graft preservation methods have contributed to a steady decrease in blood transfusion requirements in most liver transplant programs. Several centers are now reporting liver transplantation without any need for blood transfusion in up to 30% of their patients. Despite these improvements, most patients undergoing liver transplantation still require blood transfusions that have a negative impact on outcome, emphasizing the need for further attempts to control blood loss by surgeons and anesthesiologists. This paper provides an overview of the clinical and research developments, which have contributed to a reduction in blood loss and transfusion requirements, resulting in an important reduction in morbidity and mortality after liver transplantation during the last two decades.
Abstract: The aim of this study was to analyze the effect of human leukocyte antigen (HLA) class I and HLA-DR mismatching, sharing cross-reactive antigen groups (CREGs), and sharing HLA-DR antigens on the outcome after pediatric liver transplantation. Outcome parameters were graft survival, acute rejection, and portal fibrosis. A distinction was made between full-size (FSLTx) and technical-variant liver transplantation (TVLTx). A total of 136 primary transplants were analyzed. The effect of HLA on the outcome parameters was analyzed by adjusted multivariate logistic and Cox regression analysis. HLA mismatches, shared CREGs, and shared HLA-DR antigens affected neither overall graft survival nor survival after FSLTx. Survival after TVLTx was superior in case of 2 mismatches at the HLA-DR locus compared to 0 or 1 mismatch (P = 0.01) and in case of no shared HLA-DR antigen compared to 1 shared HLA-DR antigen (P = 0.004). The incidence of acute rejection was not influenced by HLA. The incidence of portal fibrosis could be analyzed in 62 1-yr biopsies and was higher after TVLTx than FSLTx (P = 0.04). The incidence of portal fibrosis after TVLTx with 0 or 1 mismatch at the HLA-DR locus was 100% compared to 43% with 2 mismatches (P = 0.004). After multivariate analysis, matching for HLA-DR and matching for TVLTx were independent risk factors for portal fibrosis. In conclusion, an overall beneficial effect of HLA matching, sharing CREGs, or sharing HLA-DR antigens was not observed. A negative effect was present for HLA-DR matching and sharing HLA-DR antigens on survival after TVLTx. HLA-DR matching might be associated with portal fibrosis in these grafts.
Abstract: Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose-finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double-blind trial, patients with end-stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 microg/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty-three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required.
Abstract: Pancreatic cystic tumors commonly include serous cystadenoma (SCA), mucinous cystadenoma (MCA), and mucinous cystadenocarcinoma (MCAC). A differential diagnosis with pseudocysts (PC) can be difficult. Radiologic criteria are not reliable. The objective of the study is to investigate the value of cyst fluid analysis in the differential diagnosis of benign (SCA, PC) vs. premalignant or malignant (MCA, MCAC) lesions.
Abstract: Congenital absence of the portal vein (CAPV) is a very rare venous malformation in which mesenteric venous blood drains directly into the systemic circulation. There is no portal perfusion of the liver and no portal hypertension. This abnormality is usually coincidentally discovered in children, the majority of whom have no signs of encephalopathy and only slightly abnormal liver function tests. Additional anomalies common in CAPV are cardiovascular abnormalities and hepatic tumors. To date, only 5 adult patients (>18 years) with CAPV have been described, none of whom underwent liver transplantation. We describe a 45-year-old man with CAPV and end-stage renal insufficiency due to focal segmental glomerulopathy, who developed therapy-resistant encephalopathy with intermittently high ammonia levels. The patient underwent a combined liver and kidney transplantation and is doing well at 2.5 years of follow-up. Histopathological examination of the native liver showed no portal vein branches in the portal tracts. In conclusion, our experience suggests that, although children with CAPV usually have no symptoms of encephalopathy, this may still develop at a later stage in adult life. When encephalopathy becomes refractory to medical therapy, orthotopic liver transplantation (OLT) can be successfully performed with restoration of normal cerebral function.
Abstract: From September 1986 until December 2001, 42 patients (20 males and 22 females) underwent a combined extrahepatic bile duct resection (EHBDR) and liver resection (LR) for hilar cholangiocarcinoma (HC). The aim of this study was to analyze patient survival, morbidity, and mortality as well as to seek predictive factors. The 1-, 3-, and 5-year actuarial patient survival was 72%, 37%, and 22%, respectively. Median survival was 19 months. Hospital mortality, all due to septic complications, was 12%. Morbidity was observed in 32 patients (76%). Infections were the most dominant complication. Patients (n=11) with American Joint Committee on Cancer (AJCC) stage I or stage II tumors exhibited a superior survival compared with patients (n=31) with stage III or IV tumors (p=0.023). Patients with tumor-free lymph nodes (n=26) indicated a greater survival compared with patients with tumor-positive lymph nodes (n=16) (p=0.004). Patients undergoing vascular reconstructions indicated a trend toward higher mortality and lower survival (p=0.068). Over 20% of the patients with hilar cholangiocarcinoma can survive more than 5 years after a combined EHBDR and LR at the cost of 12% perioperative mortality and a 76% morbidity. Results might improve with the prevention of infectious complications and improved selection of patients to avoid vascular reconstruction and to predict a negative nodal state.
Abstract: Uncontrolled activation of matrix metalloproteinases (MMPs) can result in tissue injury and inflammation, yet little is known about the activation of MMPs during orthotopic liver transplantation (OLT). OLT is associated with increased fibrinolytic activity due to elevated plasmin generation. The serine-protease plasmin not only causes degradation of fibrin clots but is also thought, amongst others, to play a role in the activation of some matrix metalloproteinases. We therefore studied the evolution of MMP-2 and -9 plasma concentrations during OLT and the effect of serine-protease inhibition by aprotinin on the level and activation of these MMPs. In a group of 24 patients who participated in a randomized, double-blind, placebo-controlled study we determined serial MMP-2 and MMP-9 plasma levels during transplantation using ELISA (total MMP), activity assays (activatable MMP) and zymography. In addition, the MMP-inhibitors TIMP-1 and TIMP-2 were assessed by ELISA. The putative regulating factors tumor necrosis factor alpha (TNF-alpha) and tissue-type plasminogen activator (t-PA) were assessed as well. Patients were administered high-dose aprotinin, regular-dose aprotinin or placebo during surgery. Plasma TIMP-1, TIMP-2 and MMP-2 level gradually decreased during transplantation. Approximately two-thirds of total MMP-2 appeared to be in its activatable proMMP form. No release of MMP-2 from the graft could be detected. In contrast, plasma levels of MMP-9 increased sharply during the anhepatic and postreperfusion periods. Peak MMP-9 levels of about eight times above baseline were found at 30 minutes after reperfusion. Most MMP-9 appeared to be in its active/inhibitor-complexed form. No significant differences were observed between the three treatment groups. However, in patients with more severe ischemia/reperfusion (I/R) injury the MMP-9 concentration, particularly of the active/inhibitor-complexed form, remained high at 120 minutes postreperfusion compared to patients with no or mild I/R injury. The decrease in plasma levels of MMP-2, TIMP-1 and TIMP-2 during OLT occurred irrespective of the severity of the I/R injury. There was a significant correlation between MMP-9 and t-PA levels, but not with TNF-alpha. In conclusion, OLT is associated with a sharp increase of MMP-9 during the anhepatic and postreperfusion periods, which coincided with the changes in t-PA. MMP-2, TIMP-1 and TIMP-2 gradually decreased during OLT. The composition of these MMPs was not altered by the use of aprotinin, suggesting that serine-protease/plasmin-independent pathways are responsible for MMP regulation during OLT. In addition, only MMP-9 seems to be involved in I/R injury during human liver transplantation.
Abstract: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation.
Abstract: The aim of this study is to analyse a single centre's experience with two techniques of liver transplantation (OLT), conventional (CON-OLT) and piggyback (PB-ES), and to compare outcome in terms of survival, morbidity, mortality and post-operative liver function as well as operative characteristics. A consecutive series (1994-2000) of 167 adult primary OLT were analysed. Ninety-six patients had CON-OLT and 71 patients had PB-ES. In PB-ES group two revascularization protocols were used. In the first protocol reperfusion of the graft was performed first via the portal vein followed by the arterial anastomosis (PB-seq). In the second protocol the graft was reperfused simultaneously via portal vein and hepatic artery (PB-sim). One-, 3- and 5-yr patient survival in the CON-OLT and PB-ES groups were 90, 83 and 80%, and 83, 78 and 78%, respectively (p = ns). Graft survival at the same time points was 81, 73 and 69%, and 78, 69 and 65%, respectively (p = ns). Apart from the higher number of patients with cholangitis and sepsis in CON-OLT group, morbidity, retransplantation rate and post-operative liver and kidney function were not different between the two groups. The total operation time was not different between both groups (9.4 h in PB-ES vs. 10.0 h in CON-OLT), but in PB-ES group cold and warm ischaemia time (CIT and WIT), revascularization time (REVT), functional and anatomic anhepatic phases (FAHP and AAHP) were significantly shorter (8.9 h vs. 10.7 h, 54 min vs. 63 min, 82 min vs. 114 min, 118 min vs. 160 min and 87 min vs. 114 min, respectively, p < 0.05). RBC use in the PB-ES group was lower compared to the CON-OLT group (4.0 min vs. 10.0 units, p < 0.05). Except for WIT and REVT there were no differences in operative characteristics between PB-Sim and PB-Seq groups. The WIT was significantly longer in PB-Sim group compared with PB-Seq group (64 min vs. 50 min, p < 0.05); however REVT was significantly shorter in PB-Sim group (64 min vs. 97 min, p < 0.05). Results of this study show that both techniques are comparable in survival and morbidity; however PB-ES results in shorter AAHP, FAHP, REVT and WIT as well as less RBC use. In the PB-ES group there seems to be no advantage for any of the revascularization protocols.
Abstract: A few months after birth two sisters aged 5 and 9 years had developed cholestasis and abnormal liver functions with symptoms including itching and jaundice. The younger sister also developed rickets and clotting disorders. On clinical, biochemical and immunohistopathological grounds the diagnosis of 'progressive familial intrahepatic cholestasis (PFIC) type 2' was made. Medical treatment was not succesfull in reducing symptoms. An ileocolonic bypass in the younger child was not effective. Subsequently, both patients underwent partial external biliary diversion (PEBD). Except for a period of intermittent itching in the younger child, both patients remained free of symptoms 2 years after PEBD. In cases where an early diagnosis is made, PEBD could delay or even prevent the necessity of liver transplantation.
Abstract: The effect of recombinant factor VIIa (rFVIIa) on blood loss was evaluated in cirrhotic patients undergoing orthotopic liver transplantation. In the present study, we explored the effect of rFVIIa on coagulation and fibrinolysis during orthotopic liver transplantation. Coagulation factors, parameters of thrombin generation and parameters of fibrinolysis were measured in six patients who had received a single dose of 80 micro g/kg rFVIIa and in ten controls, during and after orthotopic liver transplantation. Baseline concentrations and course of coagulation factors were similar in patients and controls. Thrombin generation did not rise after the administration of rFVIIa, but showed a sharp increase after reperfusion in patients, as compared with controls. No difference in fibrinolysis was apparent between patients and controls. No evidence of diffuse intravascular coagulation was seen. We conclude that the use of rFVIIa in orthotopic liver transplantation seems to enhance thrombin generation in a localized and time-limited matter, without causing systemic coagulation.
Abstract: Besides the conventional laboratory tests, thromboelastography (TEG) is used to monitor hemostasis during liver transplantation. A previous pilot study suggested a beneficial effect of recombinant activated factor VII (rFVIIa) on transfusion requirements in liver transplantation. In the present study, we assess the effects of rFVIIa on coagulation variables and TEG. In six study patients, the prothrombin time (PT), the activated partial thromboplastin time (aPTT) and TEG variables [reaction time (r), kinetic time (k), or clot formation time, alpha angle (alpha), and maximal amplitude (MA)] were recorded before and after the administration of a bolus of 80 microg/kg rFVIIa. These patients were compared with six controls who did not receive rFVIIa. In contrast with the control group, a significant shortening of PT (P = 0.028) and aPTT (P = 0.028), r (P = 0.046) and k (P = 0.043) values, and a significant incline of the alpha angle (P = 0.028) were noticed after injection of rFVIIa, whereas MA increased not significantly (P = 0.075). rFVIIa rapidly improved coagulation variables in liver transplant patients including PT and aPTT. Of the TEG variables, r, k and alpha angle significantly improved, and MA showed a trend to increase. These data suggest that rFVIIa not only influences the speed of clot formation, but also the physical properties of the clot, which cannot be detected by routine coagulation tests.
Abstract: Surgical procedures are inevitably associated with bleeding. The amount of blood loss may vary widely between different surgical procedures and depends on surgical as well as non-surgical factors. Whereas adequate surgical haemostasis may suffice in most patients, pro-haemostatic pharmacological agents may be of additional benefit in patients with (diffuse) surgical bleeding or in patients with a specific underlying haemostatic defect. In general, surgical haemostasis and pharmacological therapies can be complementary in controlling blood loss. The use of pharmacological therapies to reduce blood loss and blood transfusions in surgery has historically been restricted to a few drugs. Antifibrinolytic agents (aprotinin, tranexamic acid and aminocaproic acid) have the best evidence supporting their use, especially in cardiac surgery, liver transplantation and some orthopaedic surgical procedures. Meta-analyses of randomised, controlled trials in cardiac patients have suggested a slight benefit of aprotinin, compared with the other antifibrinolytics. Desmopressin is the treatment of choice in patients with mild haemophilia A and von Willebrand disease. It has also been shown to be effective in patients undergoing cardiac surgery who received aspirin up to the time of operation. However, overall evidence does not support a beneficial effect of desmopressin in patients without pre-existing coagulopathy undergoing elective surgical procedures. Topical agents, such as fibrin sealants have been successfully used in a variety of surgical procedures. However, only very few controlled clinical trials have been performed and scientific evidence supporting their use is still limited. Novel drugs, like recombinant factor VIIa (eptacog alfa), are currently under clinical investigation. Recombinant factor VIIa has been introduced for the treatment of haemophilia patients with inhibitors, either in surgical or non-surgical situations. Preliminary data indicate that it may also be effective in surgical patients without pre-existing coagulation abnormalities. More clinical trials are warranted before definitive conclusions can be drawn about the safety and the exact role of this new drug in surgical patients. Only adequately powered and properly designed randomised, clinical trials will allow us to define the most effective and the safest pharmacological therapies for reducing blood loss and transfusion requirements in surgical patients. Future trials should also consider cost-effectiveness because of considerable differences in the costs of the available pro-haemostatic pharmacological agents.
Abstract: Large transfusion requirements, i.e., excessive blood loss, during orthotopic liver transplantation (OLT) are correlated with increased morbidity and mortality. Recombinant factor VIIa (rF-VIIa) has been shown to improve hemostasis in a variety of conditions, but has never been studied in liver transplantation.
Abstract: In the European Multicenter Study on the Use of Aprotinin in Liver Transplantation (EMSALT), a randomized, double-blind, placebo-controlled, prospective study, we demonstrated that aprotinin significantly reduces intraoperative blood loss during orthotopic liver transplantation (OLT). Aprotinin is metabolized in the kidney and potentially nephrotoxic at high concentrations. Renal insufficiency is a common and serious complication after OLT. It is unknown whether aprotinin increases the risk of renal failure after OLT.
Abstract: Because of the poor outcome of hepatic retransplantation, it is still debated whether this procedure should be performed in an era of donor organ scarcity. The aim of this study was to analyze outcome of hepatic retransplantation in children, to identify risk factors influencing this outcome, and to assess morbidity and causes of death.
Abstract: Aprotinin reduces blood transfusion requirements in orthotopic liver transplantation (OLT). Concern has been voiced about the potential risk for thrombotic complications when aprotinin is used. The aim of this study is to evaluate the effects of aprotinin on the two components of the hemostatic system (coagulation and fibrinolysis) in patients undergoing OLT. As part of a larger, randomized, double-blind, placebo-controlled study, we compared coagulation (fibrinogen level, activated partial thromboplastin time [aPTT], prothrombin time, and platelet count) and fibrinolytic variables (tissue-type plasminogen activator [tPA] antigen and activity, plasminogen activator inhibitor activity, and D-dimer), as well as thromboelastography (reaction time [r], clot formation time, and maximum amplitude) in 27 patients administered either high-dose aprotinin (2 x 10(6) kallikrein inhibitor units [KIU] at induction, continuous infusion of 1 x 10(6) KIU/h, and 1 x 10(6) KIU before reperfusion; n = 10), regular-dose aprotinin (2 x 10(6) KIU at induction and continuous infusion of 0.5 x 10(6) KIU/h; n = 8), or placebo (n = 9) during OLT. Blood samples were drawn at seven standardized intraoperative times. Baseline characteristics were similar for the three groups. During the anhepatic and postreperfusion periods, fibrinolytic activity (plasma D-dimer and tPA antigen levels) was significantly lower in aprotinin-treated patients compared with the placebo group. Interestingly, coagulation times (aPTT and r) were significantly more prolonged in aprotinin-treated patients than the placebo group. No difference was seen in the incidence of perioperative thrombotic complications in the entire study population (n = 137). Aprotinin has an anticoagulant rather than a procoagulant effect. Its blood-sparing (prohemostatic) effect appears to be the overall result of a strong antifibrinolytic and a weaker anticoagulant effect. These findings argue against a prothrombotic effect of aprotinin in patients undergoing OLT.
Abstract: We describe the hemodynamic features and anatomic basis of false-negative Doppler sonographic findings compared with angiographic findings in a 42-year-old woman after orthotopic liver transplantation complicated by hepatic artery thrombosis. Complete common hepatic artery thrombosis was demonstrated by Doppler sonography and digital subtraction angiography (DSA) on the first postoperative day. A thrombectomy was performed. DSA on the third day after transplantation again showed occlusion of the left hepatic artery. No perfusion was observed in the left hepatic lobe. Liver function remained normal. Doppler sonography on days 8, 10, and 16 after transplantation demonstrated arterial blood flow in both the right and left lobes of the liver, suggesting patent left and right hepatic arteries. Repeat DSA revealed that the arterial flow in the left lobe depended on large, intrahepatic shunts originating from the right hepatic artery. Apparently, shunts can develop within a few days in a transplanted liver from radiologically undetectable structures into vessel-like channels capable of supplying the entire left hepatic lobe.
Abstract: Graft reperfusion in orthotopic liver transplantation is often associated with significant hemodynamic changes, including decreased systemic vascular resistance and arterial blood pressure. Vasopressive drugs are often required to maintain adequate perfusion pressure during the early postreperfusion period. The exact mechanism of this postreperfusion syndrome is unknown, but release of bradykinin, a potent vasodilatator, via the kallikrein system may play a role. Aprotinin is a broad-spectrum inhibitor of serine proteases such as kallikrein and therefore may ameliorate the postreperfusion syndrome and reduce the need for vasopressors.
Abstract: Intraoperative hyperfibrinolysis contributes to bleeding during adult orthotopic liver transplantation. We aimed to find out whether aprotinin, a potent antifibrinolytic agent, reduces blood loss and transfusion requirements.
Abstract: Sinusoidal endothelial cell (SEC) apoptosis is a central feature of reperfusion injury in liver transplantation. Platelet sequestration occurs after transplantation with possible deleterious effects. We tested the hypothesis that platelets mediate SEC apoptosis.
Abstract: Vascular complications have a detrimental effect on the outcome after liver transplantation. Most studies focus exclusively on hepatic artery thrombosis (HAT). The current study analyzed the incidence, consequences, and risk factors for HAT, portal vein thrombosis (PVT), and venous outflow tract obstruction (VOTO) in a consecutive series of 157 pediatric liver transplantations. The overall incidence of vascular complications was 21%. The incidences of HAT, PVT, and VOTO were 10%, 4%, and 6%, respectively. Patient survival after PVT and VOTO and graft survival after HAT and PVT were less compared with survival of grafts without vascular complications. To identify risk factors for vascular complications, factors related to recipient, donor, and surgical techniques were analyzed. A low donor-recipient (D/R) age ratio, long surgical time, and use of the proper hepatic artery of the recipient for arterial reconstruction were risk factors for HAT. Young age, low weight, segmental grafts, and piggyback technique were risk factors for PVT. Fulminant hepatic failure, high D/R age and weight ratios, and use of segmental grafts were related to VOTO. Vascular complications, which occurred in 21% of the pediatric liver transplantations, had a significant impact on patient and graft survival. Size disparity between donor and recipient was an important risk factor for vascular complications, especially in the case of transplantation of segmental grafts. Patient and graft survival might improve by avoiding the identified risk factors.
Abstract: Orthotopic liver transplantation has become the treatment of choice for children with end-stage liver disease. Although results have improved the last decades, still a considerable number of children die after transplantation. The aim of this study was to analyze long-term actual survival and to identify prognostic factors for such survival rates.
Abstract: Liver transplantation is associated with excessive blood loss. In order to identify factors influencing blood loss and to provide a basis for a pilot study to evaluate recombinant activated factor VII as a haemostatic agent, a retrospective study was performed in 164 consecutive patients with cholestatic or noncholestatic liver disease, who underwent orthotopic liver transplantation at a single centre between 1989 and 1996. Transfusion of allogeneic and autologous (cell saver) blood was used as a measurement of blood loss. Transfusion requirements were associated with age, gender, primary disease, Child-Pugh classification, serum levels of activated partial thromboplastin time, antithrombin III, urea and creatinine, platelet number, year of transplantation, length of cold ischaemia time and autologous blood transfusion. Of these variables, Child-Pugh classification (P = 0.001), urea (P = 0.0007), year of transplantation (P = 0.002), cold ischaemia time (P = 0.01) and autologous blood transfusion (P < 0.0001) were independent predictors of transfusion requirements by multivariate analysis. Thus, blood loss and transfusion requirements depend primarily on the severity of liver disease, quality of the donor liver, experience of the transplantation team and use of autologous (cell saver) blood transfusion. These findings emphasize the need for appropriate drug therapy and a critical reappraisal of current transfusion policy.
Abstract: To test the hypothesis that a low rate of change of platelet counts (PCs) after admission to the intensive care unit (ICU) is associated with mortality. Low PCs are known to be associated with disease severity in critically ill patients, but the relevance of time-dependent changes of PCs has not been investigated.
Abstract: To review the normal radiologic appearance of pancreatic transplants that use portal venous and enteric drainage, and to review the appearance of a variety of postoperative complications.
Abstract: The use of University of Wisconsin (UW) solution in liver transplantation (LTX) has significantly prolonged preservation times and facilitated semielective transplant procedures. Despite this advantage potential risk factors related to the donor, recipient, or cold storage method will persist in the UW era and detrimental effects will be reflected by primary dysfunction (PDF) after LTX. Concern has been voiced about the maximum period of UW preservation in LTX and various cold ischemia times (CIT) are mentioned. To evaluate the effect of UW solution in LTX, a prospective European multicenter study was initiated in 1988 and short-term results have been reported previously. This report focuses on the long-term effects and survival of prolonged preservation with UW solution and primary function after LTX. Three hundred and fifteen LTXs were performed in 288 patients in participating European centers. Complete follow up of at least 6 years was available for 296 grafts in 277 patients. Effects of donor, preservation, and recipient risk factors on PDF including primary non-function (PNF) and initial poor function (IPF) were evaluated. Next, the effect of risk factors on graft survival (GS) was analyzed including the long-term impact of PNF and IPF using multivariate analyses and the Kaplan-Meyer method. PDF occurred in 15.2% (45/296) with PNF in 7.8% and IPF in 7.4%. Patients with IPF had a 34% lower GS at 3 months those with immediate function (IF; 58% vs 91%; P < 0.001). This difference persisted up to 6 years for patients with IPF with a 39% GS vs 72% after IF (P < 0.001). Median CIT was significantly longer in grafts with PNF compared to IPF or IF (P = 0.03). Long-term GS, however, was significantly influenced at a lower CIT threshold with a 6-year GS for CIT < or = 16 h of 67%, compared to a CIT > 16 h of 51% (P = 0.02). Other independent risk factors for the 6-year survival rate were re-LTX, ABO incompatibility, and recipient diagnosis of acute hepatic failure. In conclusion, liver patients with PNF, but not with IPF, have a significantly lower CIT. IPF is associated with a significantly lower 3 month GS compared to IF, but this difference of 34% does not further increase during a 6-year follow up. Although a short term follow up (3 months) shows that with UW solution CIT up to 18 h has no adverse effect on GS, the 6-year data clearyl suggest that CIT should be kept to less than < 16 h to avoid tetrimental effects on lang-term GS after LTX.
Abstract: To compare the results of laparoscopic cholecystectomy (LC) and open cholecystectomy (OC) for symptomatic cholelithiasis in elective surgery we performed a prospective matched-cohort study. Hundred consecutive patients who underwent LC in the period Sept. 1990-June 1992, and 100 patients who were age and sex matched and underwent an elective OC in the foregoing two years (1989-1990) were studied. The median operation time for LC (75, 40-180 min) was significantly longer than for OC (55, 20-155 min; p <0.001). Postoperative hospitalization was significantly shorter after LC (3, 1-16 days), compared with OC (7, 4-22 days; p <0.001). Conversion of LC to OC occurred in 12 (12%) patients initially scheduled to undergo LC. Complications occurred in 5 patients (5%) after LC and in 5 patients (5%) after OC. The calculated expenses (operation and postoperative hospitalization, 3rd class) were approximately fl. 3740,- for LC (excl. investments for pieces of apparatus) and fl. 6725,- for OC. This study demonstrates that LC can be performed safely with the number of complications comparable to those for OC. Bile duct injury is a serious potential threat. The main advantages of LC are the minimal trauma, with more rapid recovery. Insurers seem to benefit from reduced postoperative disability and earlier discharge.
Abstract: Although laparoscopic cholecystectomy has become a safe and effective alternative for open cholecystectomy as treatment of symptomatic cholelithiasis, it may be followed by different complications. Two cases are presented with unusual complications after laparoscopic cholecystectomy. One patient was readmitted 11 days after laparoscopic cholecystectomy with severe upper abdominal pain and a false aneurysm of a branch of the right hepatic artery. The other patient developed a recurrent subphrenic abscess 10 months after the initial operation, which eventually was shown to be caused by a lost gallstone. Although these are rare complications of laparoscopic cholecystectomy, they should be recognized as potential causes of recurrent abdominal pain, even months after the procedure.
Abstract: We investigated the role of the donor liver in the origin of platelet disorders and hemostatic defects in liver transplantation. Eighteen pigs received an orthotopic or a heterotopic, auxiliary liver graft. Liver biopsies were taken for electron microscopic studies 5-10 min after reperfusion in nine animals. Blood samples were taken from the first hepatic outflow and from the systemic circulation before and 5 min after graft recirculation. Electron microscopy did not show any evidence of microthrombi or platelet aggregation in the graft, either after orthotopic liver transplantation or after heterotopic liver transplantation. Most blood platelets, which were lying free in the sinusoids, showed cell processes and many seemed to have lost their granulae, suggesting a degree of platelet activation. There were also signs of phagocytosis of platelets by the Kupffer cells. In the hepatic outflow, platelet count was significantly lower (p < 0.05) and fibrinolytic activity significantly higher (p < 0.01), than systemic post-reperfusion values. There were no important changes in the coagulation parameters. No significant changes were found between the effects on hemostasis of orthotopic and auxiliary graft reperfusion. In the second part of the study evidence for platelet activation was found after graft reperfusion in human liver transplantation. Plasma levels of platelet factor-4 and beta-thromboglobulin increased significantly after graft reperfusion. These studies suggest that platelet disorders and increased fibrinolytic activity are the major components of the hemostatic defect after graft recirculation in liver transplantation. Sequestration of platelets in the graft is probably due to the accumulation of (activated and degranulated) platelets in the sinusoids and phagocytosis by Kupffer cells.
Abstract: We compared hemostatic changes during OLT and HLT after various periods of graft storage, to investigate whether the host liver in HLT protects the recipient from hemostatic deterioration induced by severe graft storage damage. In particular, the mechanism of fibrinolytic deterioration was investigated. The effect of prostaglandin E1 (PGE1) on these parameters was also studied.
Abstract: Bleeding in OLT is related to two different mechanisms. There is no doubt that the extensive surgical trauma plays a critical role in the origin of serious bleeding. However, this bleeding can be aggravated by defects in the hemostasis system. Hemostasis defects can be divided into those present before the operation and secondary to the underlying liver disease and those originating during the operation. Intraoperative defects can be classified according to the three main systems of hemostasis: coagulation, fibrinolysis, and platelet function. Serious problems with coagulation are clearly related to the quality of the graft and are less frequent now since better graft preservation techniques have been introduced. Adequate intraoperative monitoring and substitution therapy with plasma products is also important in controlling coagulation defects. However, problems resulting from hyperfibrinolysis seem to be of clinical importance, especially during the anhepatic stage and after graft reperfusion. While lack of hepatic clearance seems to be an important cause of t-PA increase during the anhepatic stage, enhanced release may be important for the rise after graft reperfusion. There is also evidence that decreased platelet numbers and function, especially after graft reperfusion, play a role. The clinical relevance of this finding remains to be elucidated. Finally, it has recently been demonstrated that antifibrinolytic agents may reduce intraoperative blood loss. However, the effect of aprotinin and other antifibrinolytic agents has still to be confirmed by randomized clinical studies. Future scientific research should focus on the mechanisms underlying the hemostasis defects. It can be expected that these efforts may finally result in a further reduction in the usage of blood products during liver transplantation.
Abstract: It is still not clear whether disseminated intravascular coagulation (DIC) contributes to the hemostatic disturbances in orthotopic liver transplantation (OLT). Theoretically the lack of hepatic clearance of procoagulant factors during the anhepatic period and the release of thromboplastic material from the graft might trigger DIC. During heterotopic liver transplantation (HLT) the host liver is left in situ and procoagulant factors may still be cleared; DIC, if present, may not occur until after reperfusion. The aim of the present study was to gain more insight into the underlying mechanism of the coagulation changes during liver transplantation by comparison of OLT and HLT. Thrombin-antithrombin-III complexes (TAT), and indicator of thrombin generation, fibrin degradation products (FbDP) and routine clotting times were assayed in 12 OLTs, 18 HLTs and in a control group of 10 partial hepatic resections (PHR). TAT increased dramatically after reperfusion to 136 micrograms/l in OLT and to 94 micrograms/l in HLT (p n.s.). In contrast, FbDP levels increased only in OLT, to a maximum of 13.8 micrograms/ml. Routine clotting times changed mildly and similarly in both OLT and HLT. Conclusions: Graft reperfusion triggers excessive thrombin formation, but there are no other signs of subsequent DIC. Any thrombin formed is probably rapidly inhibited by antithrombin-III. The rise in FbDP during OLT is the result of increased fibrinolysis, which occurred only in OLT and not in HLT.
Abstract: We compared blood loss and hemostasis in pigs which had undergone either orthotopic liver transplantation (OLT) (group A, n = 12) or auxiliary heterotopic partial liver transplantation (APLT) (group B, n = 11). Blood samples were taken at regular intervals during and after the operations. In both groups, nine animals survived longer than 24 h and data from these animals were used for analysis. Median (range) intraoperative blood loss was 825 ml (250-1500 ml) in OLT and 425 ml (300-750) in APLT (P less than 0.01). Routine clotting times, as the activated partial thromboplastin time, prothrombin time and thrombin time, showed no major intraoperative changes in either group. Fibrinogen levels decreased in both groups, but no significant difference was found between the two groups. The only significant difference between group A and B was a more sustained increase in fibrinolytic activity after graft recirculation in group A. Postoperatively, restoration of fibrinogen, antithrombin-III and alpha 2-antiplasmin levels was slightly faster in group B, resulting in significantly higher levels during the first day. We conclude that, in this animal model, APLT is associated with significantly lower blood loss and less severe fibrinolytic activity, than OLT. This difference might result from the lack of an anhepatic period and the reduced surgical trauma in auxiliary heterotopic liver transplantation.
Abstract: Orthotopic liver transplantation is frequently associated with hyperfibrinolysis, the origin and clinical relevance of which is largely unknown. In 20 orthotopic liver transplantations, we studied the occurrence and systemic effects of hyperfibrinolysis. Severe fibrinolysis was defined to be present when the euglobulin-clot lysis time and the whole-blood-clot lysis time, as measured by thrombelastography, were shorter than 60 and 90 min, respectively, at some time during the operation. Based on these criteria, 7 patients had minimal fibrinolysis (group I), and 13 patients had severe fibrinolysis (group II). In group II a gradual increase of tissue-type plasminogen activator (t-PA) activity was seen during the anhepatic stage, followed by an "explosive" increase immediately after graft reperfusion (P = 0.0004, compared with group I), and a reduction of plasminogen activator inhibitor (PAI) activity. Plasma degradation products of fibrinogen and fibrin increased parallel to t-PA activity, and levels were significantly higher at 45 min after graft reperfusion in group II compared with group I (P less than 0.04). Thrombin-antithrombin III complexes showed an identical steady increase in both groups, indicating that increased t-PA activity was not related to thrombin formation. A combination of increased endothelial release and reduced hepatic clearance may have caused the increased t-PA activity. The t-PA-associated destruction of fibrinogen and fibrin after graft reperfusion is consistent with the clinical signs of severe oozing often seen in this period. These observations may have important clinical implications for the treatment of bleeding in patients undergoing orthotopic liver transplantation.
Abstract: Using specific assays, we studied fibrinolytic activity in plasma and colonic mucosa biopsies of 28 patients with inflammatory bowel disease (IBD) (12 with Crohn's disease, 16 with ulcerative colitis) and 28 control patients without inflammatory bowel disease or colon malignancy. Blood coagulation was studied using standard techniques. In plasma of IBD patients significantly decreased tissue type plasminogen activator activity (t-PA) (p less than 0.02), increased plasminogen activator inhibition (PAI) (p less than 0.01) and fibrinogen (p less than 0.001), and prolonged thrombin time (p less than 0.001) and prothrombintime (p less than 0.001) were found. In colon mucosa the percentage of t-PA to urokinase type plasminogen activator (u-PA) was 80:20% in the control group and 71:29% in the IBD group in non-inflamed mucosa. In inflamed mucosa the plasminogen activator percentage was 55:45%, significantly different (p less than 0.01) from the control group. There was also a significant absolute increase in u-PA activity and decrease of t-PA activity in the inflamed mucosa compared to the control group (p less than 0.001 and p less than 0.01, respectively). Patients with inflammatory bowel disease therefore have significant changes in components of the fibrinolytic and coagulation system both systemically and locally in colon mucosa. These changes might contribute to an increased risk for thromboembolic complications and possibly to the pathogenesis of the colitis and to the local complications such as bleeding.
Abstract: Auxiliary heterotopic liver transplantation is theoretically attractive because it leaves the recipient's liver in place. The surgical trauma of hepatectomy is avoided, and failure of the graft does not necessarily lead to the death of the patient or a second, emergency transplantation. Another advantage is that matching the body sizes of the donor and the recipient is not mandatory, which increases the number of possible donors. However, previous clinical results of auxiliary liver transplantation have been poor. We performed auxiliary partial liver transplantation in six consecutive patients with end-stage chronic liver disease who were not accepted for orthotopic liver transplantation because they had massive ascites, deficient clotting function, cachexia, or poor pulmonary reserve. The donor liver was transplanted to the right subhepatic region after removal of segments II and III, and it was provided with portal and arterial blood. There were no major changes in hemodynamic measurements during surgery. The mean hospital stay after transplantation was 22.7 days (range, 14 to 29). After a mean follow-up period of 14 months (range, 5 to 23), all patients were alive, with good graft function as demonstrated by scintigraphy, Doppler ultrasonography, and synthesis of clotting factors. From these observations we conclude that auxiliary partial liver transplantation is an attractive alternative to orthotopic liver transplantation in high-risk patients. Its role in other patients who need liver transplants remains to be defined.
Abstract: In spite of its unpredictable kinetics, heparin is still not generally monitored during peripheral vascular surgery. To evaluate heparin levels and neutralisation, plasma heparin concentrations were measured using a chromogenic substate method during 20 consecutive operations on the Abdominal Aorta. This was combined with measuring activated partial thromboplastin time (APTT), thrombin time (ThT), prothrombin time (PT), antithrombin-III (AT-III) and fibrinogen concentration. Heparin concentration 5 min after administration and the elimination rate showed a wide variation. Using a standard dosage for all patients resulted in plasma heparin levels that are potentially too low in some patients. The APTT and ThT were found to be unsuitable for an exact calculation of heparin levels. Protamine administration based on the surgeon's judgement of haemostasis was inadequate. Furthermore an intraoperative decrease of AT-III and fibrinogen was seen in eight patients. It is advisable and possible to have direct monitoring of heparin concentration during peripheral vascular surgery.
