Liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in HFE hemochromatosis.

UNLABELLED: Defects in human hemochromatosis protein (HFE) cause iron overload due to reduced hepatic hepcidin secretion. Liver transplantation (LT) is a key treatment for potential complications from HFE-related hereditary hemochromatosis (HH). This study evaluated hepcidin secretion and iron burden after LT to elucidate HH pathophysiology. Patients (n=18) homozygous for the p.Cys282Tyr mutation in the HFE gene underwent LT between 1999 and 2008. Serum iron, serum hepcidin, and hepatic iron concentrations were determined before LT and at the end of follow-up (median 57 months). Mortality and causes of death were determined. Survival was compared to that of the overall patient population that received LT. Before LT, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30 nmol/L). After LT, 11 patients had iron evaluations; none received iron depletion therapy; all had normal transferrin saturation. The mean serum ferritin was 185 (± 99) µg/L. Magnetic resonance imaging showed that iron overload was absent in nine patients, mild in one patient with metabolic syndrome, and high (180 µmol/g) in one patient with hereditary spherocytosis discovered after LT. At the end of follow-up, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; P<0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at 1 and 5 years, respectively. Survival was similar for patients with HH and patients that received LT for other causes. CONCLUSION: In HH, LT normalized hepcidin secretion and prevented recurrence of hepatic iron overload. Survival was similar to that of patients who received LTs for other liver diseases.

Conversion to everolimus in maintenance liver transplant patients: a multicenter, retrospective analysis.

Data on the conversion of patients to everolimus after liver transplantation are sparse. A multicenter, retrospective study followed 240 maintenance liver transplant patients to analyze the current indications for everolimus conversion, the employed regimens and exposure levels, and the impact on efficacy and safety. The mean time from transplantation to the introduction of everolimus was 4.9 ± 5.2 years. The mean everolimus trough level was 7.3 ± 4.1 ng/mL at month 1 and 8.1 ± 4.7 ng/mL at month 12. At 12 months, 61.6% of the patients were no longer receiving calcineurin inhibitor (CNI) therapy. The mean estimated glomerular filtration rate (eGFR) according to the Cockcroft-Gault formula was 64.2 ± 30.0 mL/minute on day 0 and 68.4 ± 32.5 mL/minute at month 12 (P = 0.007). Among patients with baseline serum creatinine levels ≥ 130 µmol/L, the eGFR values were 44.3 ± 15.7 mL/minute on day 0 and 53.7 ± 26.0 mL/minute at month 12 (P = 0.003). Four patients (1.6%) developed mild or moderate biopsy-proven acute rejection. Adverse events led to everolimus discontinuation in 12.9% of the patients. After the initiation of everolimus, the mean white blood cell count decreased significantly, and the total cholesterol and triglyceride levels increased significantly. In this retrospective analysis of the largest cohort of maintenance liver transplant patients analyzed after their conversion to everolimus, more than 60% of the patients were kept free of CNIs with a very low risk of acute rejection and with an acceptable safety profile. Randomized trials in which maintenance liver transplant patients are switched to everolimus in response to clinical indications or preemptively are warranted.

Long-term renal function in liver transplant recipients and impact of immunosuppressive regimens (calcineurin inhibitors alone or in combination with mycophenolate mofetil): the TRY study.

The prevalence of renal insufficiency before and at 1, 12, and 60 months after liver transplantation (LTx; primary endpoint) and the changes in the glomerular filtration rate (GFR) at same time points according to the immunosuppressive regimen (coprimary endpoint) were investigated. The primary outcome was determined for the entire cohort, whereas the coprimary endpoint was determined only for 2 groups of patients: those who started and remained on a calcineurin inhibitor (CNI) alone, that is, the CNI-alone group (n = 624), and those who started and remained on a CNI in combination with mycophenolate mofetil (MMF), that is, the MMF group (n = 117). GFR was <60 mL/minute/1.73 kg/m(2) in 11%, 48%, 51% and 58% of the patients at baseline and at 1, 12, and 60 months, respectively. The decrease in GFR was significantly lower in the MMF group compared to the CNI-alone group at 12 and 60 months (-16% versus -30% and -15% versus -33%, respectively), whereas the GFR decrease at 1 month was not different between the 2 groups. There were no significant differences between the 2 groups in CNI doses or blood levels at 12 and 60 months. In conclusion, there was a worsening of renal failure in 83% of patients post-LTx; 58% and 5% had GFRs of <60 and <30 mL/minute/1.73 kg/m(2), respectively, at 5 years after LTx. The reduction of the GFR was significantly less marked in the MMF group compared to the CNI-alone group, and this could be related to less important CNI exposure early after LTx. It seems likely that early intervention for CNI reduction is best for reducing the use of CNIs in the long term.

Severe left-sided heart failure early after liver transplantation.

Left-sided heart failure (LHF) after liver transplantation (LT) is rare and poorly understood. We performed a case-control study. We reviewed the data of all patients with LHF after LT at our center from November 2000 to July 2007. Each case was matched to 1 LT control without LHF for age, sex, date of transplantation, and liver disease. Twenty of 599 patients developed LHF (3.3%). Pretransplant cardiovascular characteristics and risk factors were similar in cases and controls, except for the prevalence of left ventricular enlargement, which was greater in controls. At the time of diagnosis, the median left ventricular ejection fraction was 25% in cases, and increased afterload was documented by markedly elevated vascular resistances. The prevalence of infection at the time of LHF in cases was higher (55%) than in controls (10%, P = 0.02). The reported causes of LHF were infection [bacterial (n = 1) or viral (n = 7)], intraoperative cardiac arrest (n = 2), and unknown (n = 10). In comparison with their controls, cases with immediate postoperative LHF (day 0) did not have a higher Model for End-Stage Liver Disease (MELD) score (15 versus 21.5) or infection prevalence rate (17% versus 34%), whereas those with later onset LHF had a significantly higher MELD score (25.5 versus 17, P = 0.01) and infection prevalence rate (71% versus 0%, P = 0.002). Mortality was 45% in cases versus 0% in controls (P = 0.004), and the 11 cases who survived recovered from LHF. In conclusion, LHF after LT carries a high mortality risk and may have different causes. Except for immediate postoperative cases, an infection and an elevated MELD score appear to be determinant.

Molecular adsorbent recirculating system dialysis in patients with acute liver failure who are assessed for liver transplantation.

OBJECTIVE: To assess the usefulness of dialysis with the molecular adsorbent recirculating system (MARS) in patients with acute liver failure who fulfil criteria for liver transplantation. DESIGN: Observational cohort study. SETTING: ICU at a liver transplantation centre. PATIENTS: Twenty-two patients (23 episodes) received MARS dialysis. They were either listed for LT (n=14), delayed (n=1), or not listed (contra-indication, n=7). INTERVENTIONS: A total of 56 MARS treatments (median per patient 2; mean duration 7.6+/-2.6h) were performed on haemodialysis. MEASUREMENTS AND RESULTS: Clinical and biological variables were assessed before and 24[Symbol: see text]h after MARS therapy. The rate of recovery of liver function without transplantation was compared with an expected rate and survival was analysed. Following MARS dialysis, we observed an improvement in the grade of hepatic encephalopathy (P=0.02) and the Glasgow coma score (P=0.02), a decrease in conjugated bilirubin (P=0.05) and INR (P=0.006), and an increase in prothrombin index (P=0.005). Overall, liver function improved in seven patients (32%): four listed patients in whom transplantation could be avoided and three patients among those not listed due to contra-indications. The transplant-free recovery rate in listed patients was 29% (vs. expected 9%, P=0.036). Listed patients (n=14) had a higher 30-day survival rate [86% (12/14) vs 38% (3/8), P=0.05] and a higher long-term survival rate (P=0.02). CONCLUSIONS: A statistically significant improvement of liver function was observed after MARS therapy. Transplant-free recovery was more frequent than expected. The apparent benefit of MARS dialysis to treat acute liver failure needs to be confirmed by a controlled study.

[Genetic iron overload diseases: a deeply changing world]. / Les surcharges génétiques en fer: un monde en pleine mutation.

Iron overload diseases are a quickly and deeply changing world, due to major advances in genetics and molecular biology. Five main entities are concerned: a frequent one, namely HFE-related or type1 haemochromatosis, and four rare or exceptional diseases which are types 2, 3 and 4 haemochromatosis and aceruloplasminemia. Increased duodenal iron absorption and enhanced macrophagic iron recycling, both due to hypo-hepcidinemia, account for the development of cellular excess in types 1, 2, 3 haemochromatosis whereas decreased cellular iron egress is the main explanation for type 4 haemochromatosis and aceruloplasminemia. Non-transferrin bound iron plays an important role in cellular iron excess and damage. Phlebotomies remain an essential therapeutic tool but the improved understanding of the intimate mechanisms underlying these diseases open the road for innovative therapeutic approaches.

[Liver transplantation for hepatocellular carcinoma]. / Transplantation hépatique pour carcinome hépatocellulaire.

Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver. It mostly develops on cirrhotic livers. Orthotopic liver transplantation is the only treatment that definitively addresses both the metachronous occurrence risk of HCC and the underlying disease. Under Milan criteria, i.e. less than 3 nodules of 3 cm max in diameter, or 1 nodule of 5 cm maximum, OLT has been shown effective and provides with survival rates almost equal to those obtained with HCC free cirrhotic patients. In Rennes, 195 patients with early HCC on cirrhotic livers have been transplanted from January 1995 to June 2005. Global and disease free 8 years patient survival rates were 73 and 70%, respectively. These results were significantly altered when the recipient was female, the cirrhosis due to C virus and the patient of B blood group. Despite these excellent results, the principal limit to the application of transplantation for HCC remains the long period of time patients have to wait for a graft. During this period of time, growth of the tumour may drop the patient out of Milan criteria and subsequently from the waiting list. The role of chemoembolisation, liver resection and thermal ablation while the patient is waiting for a graft remains debatable.

Severe fibrosis in patients with recurrent hepatitis C after liver transplantation: a French experience on 250 patients over 15 years (the Orfèvre study).

BACKGROUND AND AIMS: Recurrent hepatitis C after liver transplantation (LT) is associated with rapid fibrosis progression. The aim of this study was to evaluate the cumulative risk for severe fibrosis and the factors influencing it. PATIENTS AND METHODS: Two hundred and fifty LT patients were included 1 to 15years after LT. Recurrence of chronic hepatitis C on liver graft was classified according to Metavir score. RESULTS: Kaplan-Meyer estimates for actuarial progression to severe fibrosis (Metavir>F3) showed a probability of 15.2% and 44.5% at 5 and 10years, respectively. Predictive factors for progression to severe fibrosis were: use of tacrolimus as main CNI, recipient age at time of biopsy<55, donor age ≥45, graft HCV re-infection<3months, biologically suspected graft re-infection and lack of response to antiviral treatment after LT. Multivariate analysis disclosed that only donor age ≥45 (hazard ratio 2.243, 95%CI 1.264-3.983, P=0.0058) and lack of response to antiviral treatment (hazard ratio 2.816, 95%CI 1.227-6.464, P=0.0146) were associated to severe fibrosis. CONCLUSIONS: Our study confirms that donor age ≥45 and lack of response to antiviral treatment after LT are major predictive factors of progression of HCV recurrence on liver graft.

[Liver transplantation: who should have it and when?]. / Transplantation hépatique: qui peut en bénéficier et quand doit-on l'envisager?

Liver transplantation is an effective treatment for both acute and chronic liver disease. Liver transplantation should be considered in cases of liver disease complicated by severe hepatocellular insufficiency or severe portal hypertension for which there is no other effective treatment. To optimize conditions for the transplantation, it must be offered at the right point in the disease course. The evaluation of potential transplant recipients is a key stage for assessing contraindications and comorbidities, some of which may be potential indications for a combined transplantation. Overall survival at 5 years is 73% for all indications combined.

Liver transplantation for hepatocellular carcinoma without preoperative tumor biopsy.

BACKGROUND: Progress in liver imaging has made pretransplantation tumor biopsy no longer systematic in patients with hepatocellular carcinoma (HCC). OBJECTIVES: Our aim was to evaluate the accuracy of a preoperative diagnosis of HCC based on clinical and radiological findings in 102 cirrhotics qualified for liver transplantation (LT) between January 1995 and August 2003 at our institution. METHODS: The diagnostic accuracy of our policy was assessed by comparing pretransplant diagnosis with the pathologic report of explanted livers. RESULTS: Sensitivity, specificity, positive, and negative predictive values for the preoperative clinical and radiological diagnosis of HCC were 89%, 94.3%, 77%, and 93.3%, respectively. A false-positive preoperative diagnosis was made in 20 of 102 patients (19.6%) (dysplastic nodules [n=9], regenerative nodules [n=5] cholangiocellular carcinoma [n=1], hemangioma [n=1], and no lesion [n=4]). All tumors larger than 3 cm were correctly diagnosed, irrespective of serum alpha-fetoprotein (sAFP) levels. The risk of overestimating the diagnosis of HCC in the subgroup of patients with tumors less than 3 cm was conversely correlated with preliver transplantation sAFP (sAFP100: 11%; sAFP>200: 0%). CONCLUSION: In cirrhotics with nodules larger than 3 cm irrespective of sAFP or nodules less than 3 cm with sAFP greater than 200 ng/L, the pretransplant diagnosis of HCC can be made without performing biopsy. In other cases (i.e., nodules less than 3 cm and sAFP lower than 200 ng/L), histologic confirmation of HCC or a close follow-up imaging should be considered.

Suppressive properties of human CD4+CD25+ regulatory T cells are dependent on CTLA-4 expression.

It has been demonstrated that T cells with regulatory properties are present within the peripheral blood CD4(+)CD25(+) T cell compartment. Here, we describe an original method to purify human CD4(+)CD25(+)CD152(+) T lymphocytes as living cells by forcing the exportation of CTLA-4 molecules stored in intracellular vesicules at the cell surface. By doing so, we demonstrate that CD4(+)CD25(+) T cells contain a smaller and more homogeneous population enriched in cells with in vitro regulatory activity. Moreover, we show that this enrichment in regulatory T cells is associated with an increased expression of Foxp3 and that CD4(+)CD25(+)CD152(+) T lymphocytes display a much stronger suppressive activity in controlling in vitro proliferation of alloantigen-specific T cells than CD4(+)CD25(+)CD152(-) T lymphocytes purified in parallel. Lastly, by purifying such cells expressing CTLA-4, we demonstrate that indeed CTLA-4 is involved in CD4(+)CD25(+)CD152(+) T cell regulatory activity, while suppressive cytokines are not.