Good outcome of liver transplantation in patients with pre-existing renal cell carcinoma.

The presence of a pre-existing or recent extra-hepatic solid tumor was considered for a long time as an absolute contraindication to liver transplantation, by fear of futility with an unacceptable increase in non-liver-related mortality. However, cancer-related mortality in solid malignancies is heterogeneous, and experts suggest that case-by-case multidisciplinary decisions should be made. Here, we report the cases of 3 patients with favorable oncological and liver outcome in patients with renal cell carcinoma detected during pre-transplant evaluation that nonetheless underwent liver transplantation.

Progressive multifocal leukoencephalopathy after liver transplantation can have favorable or unfavorable outcome.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus (JCPyV) in immunocompromised patients, including solid organ transplant recipients. We report 2 cases of PML late after liver transplantation (144 and 204 months) and review the few other published cases. The clinical course of PML is characterized by a rapid progressive neurological decline coinciding with the presence of white matter lesions on magnetic resonance images. No direct antiviral therapy is available against the JCPyV. The prognosis is therefore extremely poor. Restoration of the immune response achieved by tapering or ending the immunosuppressive therapy is the basis of treatment in transplanted patients. One of our patients is alive 3 years after diagnosis after total withdrawal of immunosuppressive therapy. The other presented severe rejection when tapering immunosuppression and died 26 months after diagnosis.

Paediatric liver transplanted patients and prevalence of hepatitis E virus.

BACKGROUND: Hepatitis E is an emerging disease in developed countries and is usually asymptomatic, particularly in children. Chronic infection is possible in immunocompromised individuals. In the context of a liver transplant, it can simulate a rejection. In this case, antiviral therapy may be considered, thus highlighting the need to diagnose hepatitis E virus (HEV) infection in this population. OBJECTIVES: Given the lack of data in France, we have studied the the prevalence of antibodies to HEV in the paediatric liver transplant population. STUDY DESIGN: This was a retrospective study, carried out in Lyon between 1st January 2010 and 31 May 2013. HEV serology (anti-HEV IgM &IgG) and HEV PCR were studied in 96 children who had undergone liver transplants (84 isolated liver and 12 combined liver and kidney transplants). RESULTS: Eight patients (8.3%; 62.5% girls; mean age:12.3 years) were HEV seropositive. The mean period since their transplantation was 10 years (range:2-21.8 years). Biliary atresia was the principal indication for transplantation. Seven of these eight children had received liver transplants. There were no differences between the epidemiological and clinical data concerning these patients and the remainder of the study population, particularly with respect to immunosuppression(7/8 tacrolimus; 50% dual immunosuppression). No cases of chronic hepatitis E were found, but 1/8 had chronic cytolysis(EBV&adenovirus infection). In all the patients tested(4/8), seroconversion had occurred after the transplant. There was no significant differences between the age groups in this study. CONCLUSIONS: This study showed that in France, the prevalence of antibodies to HEV in paediatric liver and combined liver and kidney transplant patients is 8.3%, as has been found by other European authors.

[Long-term quality of life after pediatric liver transplantation]. / Qualité de vie à long terme après transplantation hépatique chez l'enfant.

We assessed quality of life in children after liver transplantation (LT) for at least 5years and in their parents, taking into account the physical, psychological, and social components, then compared the results of the patients with those of the general population and investigated the association between quality of life and somatic and psychosocial factors. Thirty-three patients, aged 8 to 18years and with a mean follow-up of 11.4years were included. Quality of life was assessed using generic self-administered questionnaires in 3 versions depending on age (pre-teens, teens, parents): the AUQUEI, OK Ado, and SQLP, respectively. Patient quality of life improved with age for all components and adolescent patients could exceed that of the general population. There was a negative impact of LT on parental quality of life, but family cohesion was strengthened. The parameters associated with patient quality of life were primarily psychosocial parameters, with special consideration for siblings and school. The somatic parameters related to LT had little impact on the quality of life of the patients but were strongly correlated with parental scores, especially when there were complications related to LT or immunosuppression. Quality-of-life assessment is complementary to clinical and laboratory data and is essential to optimize patient monitoring. Parental assessment is essential because of the long-term impact of LT on these families. A regular assessment of the quality of life of young liver transplant recipients is necessary to determine whether the encouraging results are confirmed on a larger cohort.

Anatomy of the right liver lobe: a surgical analysis in 124 consecutive living donors.

BACKGROUND: Understanding anatomic variations of the right lobe is fundamental in adult to adult living donor liver transplantation. METHODS: We analysed anatomy in 124 right liver (RL) donors. RESULTS: Portal vein: normal anatomy was found in 85.5% donors. In 14.5% the main right portal vein (PV) was absent. Hepatic artery: single arterial inflow of the RL was identified in 96% of donors. In 4% two arterial stumps were found. Bile duct: classic anatomy was identified in 50.8% of donors; 9.7% had a trifurcation of the common bile duct; in 7.2% the right anterior and in 15.3% the right posterior bile duct opened into the left bile duct; one segmental bile duct opened directly into the common bile duct in 12.1% and two segmental bile ducts in 4.8%. Hepatic veins (HV): in 74.3% the right HV was the single outflow; in 24.2% significant accessory HV (>5 mm) were preserved, in 2.4% the middle HV was harvested. We found that patients with PV variations had high incidence of multiple bile ducts (88.9%) while patients with single right PV had lower incidence (42.4%) (p = 0.00026). CONCLUSION: While anatomic variations in the RL donor were common, no contraindication to RL harvesting was noted in this study.

Introduction of mycophenolate mofetil in maintenance liver transplant recipients: what can we expect? Results of a 10-year experience.

BACKGROUND: Mycophenolate mofetil (MMF) is a cornerstone immunosuppressive drug after liver transplantation (OLT). The aim of this study was to evaluate the long term results of the addition of MMF in maintenance OLT recipients. METHODS: From 1996 to 2006, MMF was introduced because of (1) histologic features of rejection or (2) calcineurin inhibitor (CNI) toxicity in order to reduce CNI dosage. RESULTS: The study population included 208 patients (median, age 54 ± 9 years), with a median delay between OLT and MMF introduction of 54 ± 43 months. The median dosage of MMF was 1180 mg/d at the end of follow-up. After a median follow-up of 50 ± 26 months, 26.4% of the patients taking MMF did present ≥1 side effect and MMF discontinuation rate was 13.8% (transient in 3.8%). The main side effects were digestive disorders (45%), pruritus ± rash ± mucitis (12.7%), and myelosuppression (16.4%). MMF was withdrawn because of digestive disorders (17.2%), pruritus ± rash ± mucitis (17.2%), and myelosuppression (24.1%). The mean glomerular filtration rate as calculated by the Cockcroft-Gault formula value significantly increased after the introduction of MMF (58.1 vs 71.4 mL/min; paired t-test; P < .01). Improvement of renal function was significantly associated with initial association with tacrolimus (vs cyclosporine), initial trough level of cyclosporine (not tacrolimus), delay between OLT and MMF introduction, and age of renal impairment. CONCLUSION: Our results suggest that the introduction of MMF in OLT maintenance recipients is efficient and well-tolerated (one quarter of the patients presented significant side effects, leading to treatment discontinuation in 10% of the patients).

Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation.

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

Liver transplantation for multiple angiomyolipomas complicating tuberous sclerosis complex.

Tuberous sclerosis complex is a genetic multisystem disorder characterised by widespread hamartomas in several organs, including the brain, heart, skin, eyes, kidney, lung, and liver. Hepatic multiple, bilateral angiomyolipomas are a rare and usually asymptomatic complication in patients with tuberous sclerosis. We report here the case of a patient who needed liver transplantation because of debilitating manifestations and mechanical complications of massive liver involvement by multiple angiomyolipomas (severe malnutrition, anorexia and abdominal pain). Seventeen tumors, from 2 to 16 cm in diameter, were identified at examination of the liver explant. No feature suggestive of malignant behaviour was identified at histological examination. In conclusion, this unusual indication of liver transplantation underlines the interest of this therapeutic approach for benign tumors for which the multiplicity of the lesions and their huge volume prevent any attempt at surgical resection.

Matrix metalloproteinase 2 in reduced-size liver transplantation: beyond the matrix.

We studied the contribution of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) to the beneficial effects of preconditioning (PC) in reduced-size orthotopic liver transplantation (ROLT). We also examined the role of c-Jun N-terminal kinase (JNK) and whether it regulates MMP2 in these conditions. Animals were subjected to ROLT with or without PC and pharmacological modulation, and liver tissue samples were then analyzed. We found that MMP2, but notMMP9, is involved in the beneficial effects of PC in ROLT. MMP2 reduced hepatic injury and enhanced liver regeneration. Moreover, inhibition of MMP2 in PC reduced animal survival after transplantation. JNK inhibition in the PC group decreased hepatic injury and enhanced liver regeneration. Furthermore, JNK upregulated MMP2 in PC. In addition, we showed that Tissue inhibitors of matrix metalloproteinases 2 (TIMP2) was also upregulated in PC and that JNK modulation also altered its levels in ROLT and PC. Our results open up new possibilities for therapeutic treatments to reduce I/R injury and increase liver regeneration after ROLT, which are the main limitations in living-donor transplantation.

New insights into fatty liver preservation using Institute Georges Lopez preservation solution.

Institute Georges Lopez preservation solution (IGL-1) has been demonstrated to be useful for fatty liver preservation. The mechanisms responsible for this effective graft protection against ischemia-reperfusion injury are pivotal actions on generation of nitric oxide a diffusible molecule with vasodilator properties, that facilitates the up-regulation of other well-known cytoprotective genes, such as hypoxia-inducible factor-1 alpha (HIF-1alpha) and heme-oxygenase 1 (HO-1). During normoxic reperfusion, the presence of nitric oxide permits HIF-1alpha accumulation to inhibit prolyl-hydoxylases, thus promoting an additional overexpression of the HO-1 in steatotic and nonsteatotic graft livers preserved in IGL-1.

Extra-anatomical hepatic artery reconstruction following post-embolization iatrogenic dissection and arterial anastomotic rupture in two liver transplant recipients.

When hepatic artery reconstruction is required during hepatic transplantation, this is generally performed with donor vessels. We describe two cases requiring a prosthesis. The first case was a 58-year-old man transplanted for cirrhosis complicated by hepatocellular carcinoma. During transplantation, dissection of the celiac trunk occurred due to arterial embolization and the use of the patient's vessels was impossible. An extra-anatomical bypass between the infra-renal aorta and the donor hepatic artery was performed via the interposition of a graft tube. The second case was a 52-year-old man transplanted for cirrhosis complicated by hepatocellular carcinoma. On day 16, a ruptured anastomosis was suspected and the patient underwent emergency revision laparotomy. Arterial revascularisation was performed with an aortohepatic bypass using a synthetic GoreTex((R)) graft. Patient follow-up was uneventful.

Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report.

Liver transplantation (LTx) for metastatic endocrine tumors (MET) remains controversial due to the lack of clear selection criteria. From 1989 to 2005, 85 patients underwent LTx for MET. The primary tumor was located in the pancreas or duodenum in 40 cases, digestive tract in 26 and bronchial tree in five. In the remaining 14 cases, primary location was undetermined at the time of LTx. Hepatomegaly (explanted liver > or =120% of estimated standard liver volume) was observed in 53 patients (62%). Extrahepatic resection was performed concomitantly with LTx in 34 patients (40%), including upper abdominal exenteration (UAE) in seven. Postoperative in-hospital mortality was 14%. Overall 5-year survival was 47%. Independent factors of poor prognosis according to multivariate analysis included UAE (relative risk (RR): 3.72), primary tumor in duodenum or pancreas (RR: 2.94) and hepatomegaly (RR: 2.63). After exclusion of cases involving concomitant UAE, the other two factors were combined into a risk model. Five-year survival rate was 12% for the 23 patients presenting both unfavorable prognostic factors versus 68% for the 55 patients presenting one or neither factor (p < 10(-7)). LTx can benefit selected patients with nonresectable MET. Patients presenting duodeno-pancreatic MET in association with hepatomegaly are poor indications for LTx.

Long-term results of liver transplantation for Wilson's disease.

UNLABELLED: Wilson's disease is a hereditary defect in hepatic copper metabolism, causing hepatic, neurological and/or psychiatric manifestations. For patients with severe disease, liver transplantation is the treatment of choice. The aim of this study was to report the long-term outcome of patients who underwent liver transplantation for Wilson's disease. PATIENTS AND METHODS: Thirteen patients with Wilson's disease, transplanted in Lyon France between January 1987 and May 2006, were including in this study: eight women and five men, aged eight to 53 years (median 20 years, seven children and six adults). The diagnosis of Wilson's disease was established before liver transplantation. RESULTS: The indication for liver transplantation was chronic (69%) or fulminant liver failure (31%). The median follow-up after liver transplantation was 10 years with 100% patient survival. Copper metabolism returned to normal in all patients. None of the patients with exclusive liver disease required chelation treatment after liver transplantation and none developed neurological symptoms of Wilson's disease. CONCLUSION: Liver transplantation totally reverses the abnormalities of copper metabolism and subsequent hepatic failure, but the course of neurological symptoms remains unpredictable. Long-term patient survival can be excellent without occurrence of neurological complications.

Transoesophageal echo-Doppler vs. thermodilution cardiac output measurement during hepatic vascular exclusion in liver transplantation.

BACKGROUND AND OBJECTIVE: Continuous monitoring of cardiac output during liver transplantation is essential to evaluate the patient's haemodynamic tolerance to acute volume variations. The aim of this study was to compare the cardiac output values obtained with a transoesophageal echo-Doppler and those obtained with a continuous thermodilution cardiac output pulmonary artery catheter. METHODS: Twenty adult patients were prospectively studied during a 5 min hepatic vascular exclusion test performed at the end of the dissection phase. Echo-Doppler and continuous thermodilution cardiac output, mean arterial pressure and end-tidal CO2 were measured before and at the end of the test. RESULTS: Before the test, echo-Doppler cardiac output was 7.0 +/- 2.7 L min(-1) and thermodilution was 9.4 +/- 3.1 L min(-1), (R = 0.85, P < 0.001). The end test values were, respectively, 3.5 +/- 2.7 and 7.8 +/- 3.5 L min(-1) (R = 0.23, P = 0.34). Bland and Altman analysis showed a bias of -2.2 before the test, which increased to -4.4 at the end of the test. Mean arterial pressure decreased from 85.5 +/- 15 to 66.8 +/- 16 mmHg, end-tidal CO2 from 31.4 +/- 2.3 to 23.8 +/- 2.7 mmHg. CONCLUSION: Echo-Doppler cardiac output values are different from those measured by thermodilution cardiac output in these patients. Echo-Doppler cardiac output monitoring seems to detect the output changes, which can occur during acute haemodynamic changes more rapidly than thermodilution cardiac output in the course of liver transplantation.

Rejection under alpha interferon therapy in liver transplant recipients.

Interferon alpha (IFN) is the corner stone drug for the treatment of recurrent hepatitis C (HCV) in liver transplant (LT) recipients. One of its serious potential adverse effects is acute and chronic rejection. The aim of this study was to review our experience using IFN-based therapy, in order to examine the incidence and the risk factors for rejection, and the outcome of patients who developed rejection. Between September 1990 and December 2004, 70 LT recipients were treated. Patients started antiviral treatment 16 (1-137) months after LT. Histological follow-up was available in all patients according to protocol biopsies. Rejection was diagnosed and graded according to Banff classification. Twenty-one percent of patients developed acute rejection (5 mild, 9 moderate and 1 severe) during IFN-based therapy. Patients were treated for 8 (1-15) months prior to rejection. Previous history of acute rejection before IFN therapy and treatment with pegylated-IFN was significantly associated with rejection (p = 0.04 and p = 0.02, respectively). The rejection was successfully treated in 87% of patients. No chronic rejection or graft losses were observed. Acute rejection under IFN-based therapy often occurs in LT recipients, but early diagnosis with protocol biopsies and early treatment can lead to a favorable outcome.

Favorable outcome of liver transplantation despite a high hepatitis B virus replication: beyond the limits?

Patients with end-stage liver disease due to chronic hepatitis B virus (HBV) infection with a persistent viral replication are generally denied liver transplantation (LT). We report the case of a patient who presented with the emergence of a YMDD escape mutant virus under lamivudine treatment, and developed terminal liver failure requiring LT. Pre-LT introduction of adefovir led to only a mild decrease in replication. The patient was treated with a combination of intravenous hepatitis B immune globulin (HBIG) that was started perioperatively, and also continued lamivudine and adefovir after LT. One year after LT, there was no evidence of HBV infection recurrence. This observation suggests that persistent high HBV replication might not be a contra-indication to LT, providing adequate and effective prophylaxis is given, using HBIG and antiviral drug combination therapy.

Plasma ribavirin concentrations during treatment of recurrent hepatitis C with peginterferon alpha-2b and ribavirin combination after liver transplantation.

After liver transplantation (LT) for hepatitis C virus (HCV)-related cirrhosis, recurrence of HCV infection is universal. The efficacy of antiviral therapy in this indication is usually reduced because of its poor tolerability. We present herein the results of plasma measurement of ribavirin levels in transplanted patients when using increasing dosage of ribavirin, in comparison with a control cohort of nontransplanted patients. Seventeen control patients (nine women and eight men, median age 51.5 years) were compared with 12 liver transplant patients (2 women and 10 men, median age 55 years). In 76% of patients, HCV infection was genotype 1. All patients were treated by a combination of ribavirin and pegylated-interferon alpha-2b. A total of 54 blood samples were taken (1.8 per patient) for ribavirin level measurement. A virological response was obtained in 8/17 patients in the control group and in 6/12 LT patients. Ribavirin dose was lower in the LT group (8.79 vs 12.98 mg/kg/day), but plasma levels were the same in both groups (2.23 vs 2.43 mg/L for LT and non-LT groups, respectively). This was probably related to impaired renal function in the LT group (serum creatinine: 112.6 vs 73.6 micromol/L). No discontinuation of ribavirin therapy was observed and haemoglobin level was the same in both groups (109.5 g/L in LT patients vs 119.5 g/L in the control group). These results strongly support the interest in plasma measurement of ribavirin concentration during antiviral therapy in LT patients. Ribavirin dosage might be adapted without compromising its efficacy.

Spontaneous baroreflex cardiac sensitivity in end-stage liver disease: effect of liver transplantation.

BACKGROUND AND OBJECTIVE: End-stage liver disease is associated with an imbalance in the autonomic nervous system. The purpose of this study was to estimate the effect of liver transplantation on this imbalance. METHOD: The study involved 10 patients undergoing liver transplantation and 9 patients without liver impairment undergoing liver surgery. The spontaneous baroreflex sensitivity was measured before and 1 month after surgery for the liver surgery group; before and 1, 3, 6, 12 and 18 months after orthotopic liver transplantation. RESULTS: The spontaneous baroreflex slope of patients with end-stage liver disease was decreased before liver transplantation compared to the liver surgery group (3.9 +/- 2.5 ms mmHg(-1) vs. 9.9 +/- 5.0 ms mmHg(-1), P = 0.002). The mean slope was significantly increased at 12 and 18 months compared to the pre-transplantation value (3.9 +/- 2.5 ms mmHg(-1) vs. 8.1 +/- 6.6 ms mmHg(-1) and 7.4 +/- 4.8 ms mmHg(-1), respectively; P = 0.042). Nevertheless, further analysis of individual data showed that only four patients exhibited a marked increase in their baroreflex slope 12 months after the liver transplantation whereas it remained decreased in the six others. CONCLUSIONS: These results confirm that the baroreflex sensitivity is depressed in end-stage liver disease in line with an autonomic nervous system imbalance. The liver transplantation reverses this disturbance only in some patients.

Unresectable hepatocellular carcinoma: survival and prognostic factors after lipiodol chemoembolisation in 89 patients.

BACKGROUND: The majority of patients with hepatocellular carcinoma are not eligible for surgical radical treatment (resection or liver transplantation) and lipiodol chemoembolisation is an efficient alternative procedure in this indication. AIMS: To identify prognostic factors in patients treated with lipiodol chemoembolisation. PATIENTS AND METHODS: During 10 years, 89 consecutive patients with unresectable hepatocellular carcinoma underwent lipiodol chemoembolisation as a single treatment. There were 80 males and 9 females, with a median age of 65 years. Treatment consisted of one to six courses of hepatic intra-arterial lipiodol with doxorubicine and gelatin sponge. RESULTS: The median survival was 13 months with a 13.6% survival rate at 4 years. Univariate analysis showed that serum levels of albumin, bilirubin, alkaline phosphatase and alpha-fetoprotein, Child's class, tumour type, tumour size and intensity of lipiodol capture after the first course of lipiodol chemoembolisation were significant prognostic factors of survival. In the multivariate analysis, four parameters remained associated with a significantly better outcome: Child's class A, largest lesion<5 cm, uninodular tumour and intense lipiodol capture. CONCLUSIONS: While lipiodol chemoembolisation is associated with good results only in some patients, in the absence of lipiodol capture, it should be ruled out.

[Kaposi's sarcoma and organ transplantation: 22 cases]. / Maladie de Kaposi et transplantation d'organes: 22 cas.

BACKGROUND: The discovery of the Human Herpes virus 8 (HHV8) improved our knowledge of the pathogenesis of Kaposi's sarcoma. After organ transplantation, Kaposi's sarcoma exhibits distinctive features compared with other forms of the disease. PATIENTS AND METHODS: We report 22 cases of post-transplant Kaposi's sarcoma (12 kidneys, 2 kidney-pancreas, 6 livers and 2 hearts). The aim of this retrospective study was to analyze clinical and virological characteristics in these transplant patients and to specify the frequency of HHV8 seroconversions in this population. RESULTS: Twenty-one patients showed cutaneous lesions and 9 had visceral involvement. HHV8 serology was positive in 16/20 patients at transplantation and in 21/22 cases at the time of Kaposi's sarcoma diagnosis. Most cases corresponded to viral reactivations whereas seroconversions occurred in 2 cases and may have been linked to viral transmission by the graft. Treatment led to recovery in 68p. 100 of the cases. Two heart-transplant patients died from their disease. We included in our series two cases of re-transplanted patients without recurrence of Kaposi's sarcoma and one case of familial Kaposi's sarcoma. DISCUSSION: Seroconversions after transplantation emphasize the interest of systematic screening of HHV8 serology in transplant recipients and their donors.