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.

Dunnigan lipodystrophy syndrome: French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).

Dunnigan syndrome, or Familial Partial Lipodystrophy type 2 (FPLD2; ORPHA 2348), is a rare autosomal dominant disorder due to pathogenic variants of the LMNA gene. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins), is to provide health professionals with a guide to optimal management and care of patients with FPLD2, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Dunnigan syndrome is characterized by a partial atrophy of the subcutaneous adipose tissue and by an insulin resistance syndrome, associated with a risk of metabolic, cardiovascular and muscular complications. Its prevalence, assessed at 1/100.000 in Europe, is probably considerably underestimated. Thorough clinical examination is key to diagnosis. Biochemical testing frequently shows hyperinsulinemia, abnormal glucose tolerance and hypertriglyceridemia. Elevated hepatic transaminases (hepatic steatosis) and creatine phosphokinase, and hyperandrogenism in women, are common. Molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations. Regular screening and multidisciplinary monitoring of the associated complications are necessary. Diabetes frequently develops from puberty onwards. Hypertriglyceridemia may lead to acute pancreatitis. Early atherosclerosis and cardiomyopathy should be monitored. In women, polycystic ovary syndrome is common. Overall, the management of patients with Dunnigan syndrome requires the collaboration of several health care providers. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are described to provide such a support.

The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study.

INTRODUCTION: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.

The negative impact of HBV/HCV coinfection on cirrhosis and its consequences.

BACKGROUND: Hepatitis B virus (HBV)/hepatitis C virus (HCV) confection has been rarely studied in nonasian series. AIM: To compare the characteristics of HBV/HCV coinfected patients to those of HBV- or HCV-monoinfected patients in the ANRS CO22 HEPATHER cohort study. PATIENTS AND METHODS: Of the 20 936 included patients, 95 had HBV/HCV coinfection (hepatitis B surface antigen, anti-HCV antibody and HCV RNA positive) and were matched with 375 HBV- and 380 HCV-monoinfected patients on age, gender and time since HBV or HCV diagnosis. RESULTS: F3-F4 fibrosis was more frequent in coinfected patients (58%) than in HBV- (32%, P < .0001), but similar in HCV-monoinfected patients (52%, P = .3142). Decompensated cirrhosis was more frequent in coinfected patients (11%) than in HBV- (2%, P = .0002) or HCV- (4%, P = .0275) monoinfected patients. Past excessive alcohol use was more frequent in coinfected patients (26%) than in HBV (12%, P = .0011), but similar in HCV monoinfected patients (32%, P = .2868). Coinfected patients had a higher proportion with arterial hypertension (42%) than HBV- (26%) or HCV-monoinfected patients (25%) (P < .003). Multivariable analysis confirmed the association between F3-F4 fibrosis and HCV infection in HBV-infected patients (OR = 3.84, 95% CI 1.99-7.43) and the association between decompensated cirrhosis and coinfection in HBV infected (OR = 5.58, 95% CI 1.42-22.0) or HCV infected patients (OR = 3.02, 95% CI 1.22-7.44). CONCLUSIONS: HCV coinfection harmfully affects liver fibrosis in HBV patients, while decompensated cirrhosis is increased in coinfected patients compared with HBV- or HCV-monoinfected patients. HCV treatment is as safe and effective in coinfected as monoinfected patients and should be considered following the same rules as HCV monoinfected patients.

Cost-effectiveness and budget impact of interferon-free direct-acting antiviral-based regimens for hepatitis C treatment: the French case.

We evaluated the cost-effectiveness and the budget impact of new DAA-based regimen use in France. A Markov model simulated chronic hepatitis C (CHC) treatment interventions with IFN-based and IFN-free regimens at stage of fibrosis ≥F3, ≥F2 or regardless of fibrosis stage, and treatment either with the least or the most expensive combination. It estimated quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). It also assessed the budget impact over 5 years of treating all CHC-screened patients, regardless of fibrosis, assuming ≤20 000 patients treated/year and priority to ≥F3. Sensitivity analyses were also conducted. For genotypes (G) 1-4, the initiation of IFN-free regardless of fibrosis was a cost-effective strategy compared to prior standard of care (SOC) initiated at stage F2: €40 400-88 300/QALY gained in G1; similar results were obtained for patients infected with G4. Considering G2-3, the most cost-effective strategy was IFN-based regimens regardless of fibrosis compared to prior SOC initiated at stage F2: €21 300 and €19 400/QALY gained, respectively; the strategy with IFN-free regimens being more effective but not cost-effective at current costs. The budget impact of treating all CHC-screened patients over 5 years would range between 3.5 and 7.2 billion €, depending on whether one considers the least or the most expensive combination of new DAAs and whether one treats G2-3 with IFN-based or IFN-free new DAAs. In France, treatment initiation with new DDAs regardless of fibrosis stage is cost-effective, but would add 3.5-7.2 billion € to an already overburdened medical care system.

Meta-analysis: the impact of IL28B polymorphisms on rapid and sustained virological response in HCV-2 and -3 patients.

BACKGROUND: Recent studies suggested that IL28B polymorphisms may affect rapid and sustained virological response rates in HCV patients infected with genotype 2 or 3. AIM: To assess the role of IL28B polymorphisms on the virological response in HCV-2 and -3 patients. METHODS: We performed meta-analysis of studies evaluating the impact of rs12979860 and rs8099917 polymorphisms on rapid and sustained virological response in HCV-2 or -3 patients. RESULTS: Twenty-three studies involving 3042 patients were included. The first meta-analysis evaluated the impact of rs12979860 polymorphism and included 1963 patients. When compared with rs12979860 CT/TT patients, CC patients had a higher rapid virological response rate (mean difference: 12.9%, 95% CI: 6.5-19.4%, P < 0.001) and a higher sustained virological response rate (mean difference: 4.9%, 95% CI: 0.1-9.8%, P = 0.046). The second meta-analysis evaluated the impact of rs8099917 polymorphism and included 2246 patients. When compared with rs8099917 TG/GG patients, TT patients had a higher rapid virological response rate (mean difference: 14.8%, 95% CI: 7.2-22.4%, P < 0.001) and a higher sustained virological response rate (mean difference: 5.5%, 95% CI: 0.4-10.6%, P = 0.033). When considering only patients treated for 24 weeks, results were unchanged. No potential sources of between-study heterogeneity were identified. CONCLUSIONS: Favourable IL28B polymorphisms are associated with higher rapid and sustained virological response rates in HCV-2 and -3 patients. However, as the impact on a sustained response is very limited, it is unlikely that IL28B polymorphisms provide additional predictive value when considering other predictors of a sustained response.

Hepatic venous pressure gradient in the assessment of portal hypertension before liver resection in patients with cirrhosis.

BACKGROUND: Preoperative measurement of hepatic venous pressure gradient (HVPG) is not performed routinely before hepatectomy in patients with cirrhosis, although it has been suggested to be useful. This study investigated whether preoperative HVPG values and indirect criteria of portal hypertension (PHT) predict the postoperative course in these patients. METHODS: Between January 2007 and December 2009, consecutive patients with resectable hepatocellular carcinoma (HCC) in a cirrhotic liver were included in this prospective study. PHT was assessed by transjugular HVPG measurement and by classical indirect criteria (oesophageal varices, splenomegaly and thrombocytopenia). The main endpoints were postoperative liver dysfunction and 90-day mortality. RESULTS: Forty patients were enrolled. A raised HVPG was associated with postoperative liver dysfunction (median 11 and 7 mmHg in those with and without dysfunction respectively; P = 0·017) and 90-day mortality (12 and 8 mmHg in those who died and survivors respectively; P = 0·026). Oesophageal varices, splenomegaly and thrombocytopenia were not associated with any of the endpoints. In multivariable analysis, body mass index, remnant liver volume ratio and preoperative HVPG were the only independent predictors of postoperative liver dysfunction. CONCLUSION: An increased HVPG was associated with postoperative liver dysfunction and mortality after liver resection in patients with HCC and liver cirrhosis, whereas indirect criteria of PHT were not. This study suggests that preoperative HVPG measurement should be measured routinely in these patients.

Randomised clinical trial: enteral nutrition does not improve the long-term outcome of alcoholic cirrhotic patients with jaundice.

BACKGROUND: Malnutrition and jaundice are independent prognostic factors in cirrhosis. AIM: To assess the impact of enteral nutrition on the survival of alcoholic cirrhotic patients with jaundice but without acute alcoholic hepatitis. METHODS: The study was a multicentre prospective randomised controlled trial comparing effects of enteral nutrition vs. a symptomatic support in patients with alcoholic cirrhosis and jaundice (bilirubin ≥51 µmol/L) but without severe acute alcoholic hepatitis. A total of 99 patients were randomised to receive either the conventional symptomatic treatment (55 patients) or the symptomatic support associated with 35 kcal/Kg/day of enteral nutrition during 4 weeks followed by an oral nutritional support during 2 months (44 patients). Randomisation was stratified on nutritional status. One-year survival curves were compared using the Kaplan-Meier method and Logrank test. RESULTS: Populations in both arms were similar. One-year survival was similar in the overall population (27/44 patients (61.4%) in the enteral nutrition arm vs. 36/55 (65.5%) in the control arm; Logrank P = 0.60) and in the subgroup suffering from malnutrition [18/29 patients (62.1%) in the enteral nutrition arm vs. 20/32 (62.5%) in the control arm; Logrank P = 0.99]. There was no statistical difference for bilirubin, prothrombin rate, Child-Pugh score, albumin or nutritional assessment. Complications during treatment (bleeding, encephalopathy, infection) occurred in 23% of patients in the enteral nutrition group (10/44) vs. 16% (9/55) of the control patients (P = 0.59). CONCLUSION: Enteral nutrition does not improve the survival and hepatic or nutritional parameters of cirrhotic patients with jaundice.

Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score.

BACKGROUND: Sorafenib increases median survival and time to radiological progression in patients with advanced hepatocellular carcinoma, but its benefit for Child-Pugh B patients remains uncertain. AIM: To evaluate the safety and efficacy of sorafenib in real-life clinical practice conditions and to assess the influence of Child-Pugh class B on safety and efficacy. METHODS: All patients treated with sorafenib for advanced hepatocellular carcinoma in our institution were included prospectively. Adverse events, overall survival and time to progression were recorded. A case control study was performed to compare outcome of patients with comparable stages of hepatocellular carcinoma, but a different Child-Pugh class. RESULTS: From March 2007 to May 2009, 120 patients were included. Overall survival was 11.1 months, Child-Pugh A patients (n=100) had significantly higher median survival than Child-Pugh B patients (n=20) (13 vs. 4.5 months, P=0.0008). In multivariate analysis, Child-Pugh class B, α-fetoprotein level and total size of lesions were independent predictive factors of death. Patients with radiological progression in the first 3 months had shorter median survival (5.4 vs. 17.4 months). In a case control study, time to symptomatic progression (2.5 vs. 3.6 months), frequency of adverse events and discontinuation of sorafenib were not correlated with Child-Pugh class. CONCLUSIONS: Patients with advanced hepatocellular carcinoma treated with sorafenib had a median survival of 11 months. Sorafenib therapy must be considered with caution in Child-Pugh B patients due to their poor survival. Radiological assessment of tumour progression at an early stage may be advantageous when tailoring sorafenib therapy.

Anti-viral therapy in haemodialysed HCV patients: efficacy, tolerance and treatment strategy.

BACKGROUND: In end-stage renal disease (ESRD) patients, hepatitis C virus (HCV) eradication improves patient and graft survival. AIM: To determine optimal use of erythropoietin (EPO) and ribavirin, to compare ribavirin concentrations with those of HCV patients having normal renal function and to evaluate sustained virological response (SVR) in a prospective observatory of ESRD candidates for renal transplantation. METHODS: Thirty-two naïve patients were treated with Peg-IFN-α2a and ribavirin. Two different schedules of ribavirin and EPO administration were used: starting ribavirin at 600mg per week and adapting EPO when haemoglobin (Hb) fell below 10g/dL (adaptive strategy) or starting ribavirin at 1000mg per week while increasing EPO from the start of treatment (preventive strategy). RESULTS: Patients treated with the adaptive strategy had lower median Hb levels (9.6 vs. 10.9g/dL, P=0.02) and more frequent median Hb levels below 10g/dL (58 vs. 5%, P=0.0007) despite lower median ribavirin doses (105 vs. 142mg/day, P<0.0001) than patients treated with the preventive strategy. There was a trend for more frequent transfusion in patients treated with the adaptive strategy than in patients treated with preventive strategy (50 vs. 20%, P=0.08). Compared to patients with normal renal function, ESRD patients had lower ribavirin concentrations during the first month (0.81 vs. 1.7mg/L, P=0.007) and similar concentrations thereafter. SVR was reached in 50%. CONCLUSIONS: Pegylated interferon (Peg-IFN) and an adapted schedule of ribavirin are effective in ESRD patients. Increasing EPO from the start of treatment provides better haematological tolerance. The optimal dosage of ribavirin remains unresolved, in light of frequent side effects.

Long-term metabolic outcome and quality of life after laparoscopic adjustable gastric banding in obese patients with type 2 diabetes mellitus or impaired fasting glucose.

BACKGROUND: The long-term outcome of type 2 diabetes mellitus after laparoscopic adjustable gastric banding (LAGB) is unknown. METHODS: A longitudinal cohort study was undertaken of patients with grade 3 obesity and type 2 diabetes or impaired fasting glucose (IFG) undergoing LAGB. Metabolic outcomes and quality of life (QoL) were assessed before and 5 years after LAGB. RESULTS: At 5 years, data for 22 out of 23 patients with type 2 diabetes and 51 out of 53 with IFG were available. Mean(s.d.) excess weight loss was 41(25) and 41(27) per cent in patients with type 2 diabetes and IFG respectively, and was associated with a significant decrease in haemoglobin (Hb) A1c, fasting and postprandial blood glucose, insulin and triglyceride levels, and in liver steatosis. There were significant increases in insulin sensitivity, beta-cell function, disposition index, high-density lipoprotein-cholesterol and QoL (Nottingham Health Profile). Good metabolic control (HbA1c 7 per cent or less) was obtained in 13 diabetic patients, but complete diabetes remission was maintained in only four. Longer duration of diabetes, and poor preoperative glucose control and beta-cell function at baseline were associated with a less favourable outcome. CONCLUSION: LAGB improved metabolic outcomes and QoL in patients with grade 3 obesity with IFG or type 2 diabetes but rarely led to prolonged remission in long-standing diabetes.

[Alcohol and the liver]. / L'alcool et le foie.

The risk of developing alcohol-induced liver injury occurs above a risk threshold around 25-30g/day. A dose-dependent relationship between alcohol intake and the risk of developing alcohol-induced liver injury is observed in alcoholic subjects with a daily consumption above this threshold. Cirrhosis is the first cause of death related to alcohol. Cirrhosis occurs more frequently in heavy drinkers disclosing alcoholic hepatitis or steatosis. Excess weight is a risk factor for alcoholic liver disease. The role of alcohol in mouth, oropharynx and oesophageal cancers is clearly established. The evidence for the role of alcohol in breast cancer has become clear. Corticosteroids improved the short-term survival of patients with severe alcoholic hepatitis. The Lille model identifies patients who will not benefit from corticosteroids. The benefit of liver transplantation is restricted to alcoholic patients with severe cirrhosis. Only abstainers are considered as candidates for liver transplantation. The recent development of non invasive methods opens up new perspectives for the screening of cirrhosis in subjects with heavy drinking.

A 2-log drop in viral load at 1 month is the best predictor of sustained response in HCV patients with normal ALT: a kinetic prospective study.

The most reliable predictor of a sustained virological response in patients with persistently normal ALT has not been identified. We analysed 17 patients with genotype 1 chronic HCV who underwent therapy with pegylated interferon alfa 2b and ribavirin for 48 weeks. Two patients discontinued therapy within 28 days because of side effects and the remaining 15 patients were analysed in detail. An analysis of on treatment virological response using area under the receiver operating characteristic analyses showed that a 2 log drop in HCV RNA at day 28 was the best predictor of a sustained virological response and a failure to reduce viral load by 2 logs correctly identified patients with a low (<15%) probability of achieving a sustained virological response. Introduction of this early discontinuation rule in patients with normal ALT would allow nearly half of the patients to discontinue futile therapy at an early stage.

Natural history and therapeutic management of recurrent hepatocellular carcinoma after liver transplantation.

While the natural history and appropriate diagnostic and management practices are relatively well defined for hepatocellular carcinoma (HCC), data are scarce concerning the characteristic features and treatment modalities for recurrent HCC after liver transplantation. The time of recurrence appears to impact survival more significantly than localization, but to date, guidelines for therapeutic management of recurrent HCC have not been established. Data in the literature shows that late and unifocal recurrence has a better prognosis when treated by surgery or radiofrequency. In the event of early recurrence, surgery cannot be recommended due to the lack of evidence and the high risk of advanced disease. Systemic therapy can be discussed in a situation of multifocal recurrence. Proliferative signal inhibitors exhibit both immunosuppressive and antiproliferative properties and liver transplantation teams tend to introduce such treatment despite the lack of extensive data.

Mycophenolate mofetil monotherapy for severe side effects of calcineurin inhibitors following liver transplantation.

Withdrawal of calcineurin inhibitors (CNI) followed by mycophenolate mofetil (MMF) monotherapy after liver transplantation (LT) remains controversial due to the increased risk of acute rejection and graft loss. The aim of the present study, performed in a large cohort of liver-transplanted patients with severe CNI-induced side effects, was to assess renal function recovery, and safety in terms of liver function, of complete CNI withdrawal and replacement by MMF monotherapy. Fifty-two patients treated with MMF monotherapy for CNI-induced toxicity were analyzed. Mean estimated glomerular filtration rate (eGFR) increased significantly during the period of MMF monotherapy, from 37 +/- 10 to 44.7 +/- 15 mL/min/1.73 m(2) at 6 months (p = 0.001) corresponding to a benefit of +17.4% in renal function. eGFR stabilized or improved in 86.5%, 81% and 79% of cases, and chronic renal dysfunction worsened in 13.5%, 19% and 21% of cases, at 6, 12 and 24 months after CNI withdrawal, respectively. Only two patients experienced acute rejection. MMF monotherapy may be efficient at reversing/stabilizing CRD, and appears relatively safe in terms of liver graft function in long-term liver-transplanted patients. However, clinicians must bear in mind the potential risk of rejection and graft loss, and should be very cautious in the management of such 'difficult-to-treat patients'.

Fatal hemophagocytic syndrome related to human herpesvirus-6 reinfection following liver transplantation: a case report.

Human herpesvirus-6 (HHV-6) has been identified as the causal agent of exanthema subitum in early childhood (also called sixth disease or roseola), a mononucleosis-like disease in adults, and as an opportunistic pathogen in transplant recipients. In the latter setting, most infections are caused by reactivation of the latent virus in the recipient and generally have a paucisymptomatic course. Only limited data on HHV-6 infection are available for liver transplant recipients. Herein we have reported a case of fatal hemophagocytic syndrome related to HHV-6 reactivation 2 weeks after liver transplantation (LT). This case suggests that this virus may be a serious and potentially life-threatening pathogen following LT.