Search

Cyrielle Caussy,1– 3 Charlène Telliam,2,4 Bader Al-Nuaimi,2 Marianne Maynard-Muet,5,6 Jérôme Dumortier,3,7 Fabien Zoulim,3,5,6 Emmanuel Disse,1– 3 Cyrille Colin,3,8 Massimo Levrero,3,5,6 Philippe Moulin1,3,4 1CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, 69495, France; 2Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hopices Civils de Lyon, Pierre-Bénite, 69495, France; 3Université de Lyon, Université Claude Bernard, Lyon, France; 4Département Endocrinologie, Diabète et Nutrition, Hôpital Cardiologique, Hospices Civils de Lyon, Bron, France; 5Service d’Hépatologie, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France; 6Centre de Recherche sur le Cancer de Lyon, INSERM, Unité 1052, CNRS, UMR 5286, Lyon, France; 7Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; 8Unité d’Evaluation Médico-Economique, Pôle Information Médicale Evaluation Recherche, Hospices Civils de Lyon, Lyon, FranceCorrespondence: Cyrielle Caussy, Service d’Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, 165 Chemin du Grand Revoyet, Pierre-Bénite, 69495, France, Tel +33478864448, Fax + 33478863019, Email cyrielle.caussy@chu-lyon.frPurpose: A systematic screening for the presence of nonalcoholic fatty liver disease (NAFLD)-related advanced fibrosis is currently recommended in patients with type 2 diabetes mellitus (T2DM) and obesity. However, real-world data of such liver fibrosis risk stratification pathway from diabetology and nutrition clinics towards hepatology clinics are scarce. Therefore, we compared data from two pathways with or without transient elastography (TE) performed in diabetology and nutrition clinics.Patients and Methods: This is a retrospective study comparing the proportion of patients with intermediate/high risk of advanced fibrosis (AF) as defined by a liver stiffness measurement (LSM) ≥ 8kPa, among patients referred in hepatology from two diabetology-nutrition departments at Lyon University Hospital, France between November 1st 2018 to December 31st 2019.Results: Among the two diabetology and nutrition departments using TE or not, 27.5% (62/225) versus 44.2% (126/285) were referred to hepatology, respectively. The pathway using TE in diabetology and nutrition referred to hepatology a higher proportion of patients with intermediate/high risk of AF compared to the pathway without TE: 77.4% versus 30.9%, p< 0.001. In the pathway with TE, the odds of patients with intermediate/high risk of AF referred to hepatology was significantly higher: OR: 7.7, 95% CI: 3.6– 16.7, p< 0.001 after adjustment for age, sex and presence of obesity and T2D compared to the pathway without TE in diabetology and nutrition clinics. However, among the patients not referred, 29.4% had an intermediate/high risk of AF.Conclusion: A pathway-referral using TE performed in diabetology and nutrition clinics, significantly improves the liver fibrosis risk stratification and avoids over-referral. However, collaboration between diabetologist, nutritionists and hepatologists is needed to avoid under-referral.Keywords: nonalcoholic fatty liver disease, FibroScan, cirrhosis, transient elastography, obesity, type 2 diabetes, screening

Summary: Background: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir‐based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. Aim: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. Methods: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease–Epidemiology Collaboration (CKD‐EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre‐treatment, on‐treatment and post‐treatment periods were 9 months, 3‐9 months and 4.5 months. Interactions between eGFR slopes and the pre‐treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On‐treatment eGFR slopes were separated in tertiles. Pre‐ and post‐treatment eGFR slopes were compared globally and according to tertiles. Results: The post‐treatment eGFR slope was significantly better than pre‐treatment eGFR slope (+0.18 (IQR −0.76 to +1.32) vs −0.11 (IQR −1.01 to +0.73) mL/min/1.73 m2/month, P = 0.03) independently of the pre‐treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child‐Pugh B and C vs lower stages, P = 0.38). Tertiles of on‐treatment eGFR slopes were −1.71 (IQR −2.54 to −1.48), −0.78 (IQR −1.03 to −0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2/month. Pre‐ and post‐treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). Conclusion: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir‐based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients. [ABSTRACT FROM AUTHOR]

Training load (TL) and recovery should be in optimal balance to obtain maximal performance gains. We aimed to study sleep as a recovery technique and its relationship with TL and performance in elite athletes. Twenty-six elite female artistic gymnasts were divided into an under 13 (n = 6), an under 14 (n = 6), a junior (n = 7; 14-15y) and a senior (=World Championship (WC) competitors, n = 7; ≥16y) category. Sleep, through sleep logs, and training parameters, using the session Rate of Perceived Exertion (sRPE) scale, were monitored to calculate total sleep time (TST), sleep efficiency (SE), TL, monotony and strain. Performance of WC competitors was evaluated through coach and WC qualification ranking. For the entire group, TST (effect sizes (ES) = -1.12, confidence intervals (CI) = -60:-47, P< .05) and SE (ES = -0.13, CI = -1.40:-0.10, P =.022) were shorter during week than weekend nights. TST and SE were highest in youngest gymnasts (P< .05). TL was lowest in under 13 and senior gymnasts (P< .05), while TL, monotony and strain were highest in junior gymnasts (P< .05). A negative regression was found between TST and TL the day after, while higher TL also led to lower TST the following night (P< .001). For the WC competitors, TST the night before the qualifications was shorter than the mean TST of the WC period (ES = -0.95, CI = -170:24, P =.030). TST correlated with coach ranking (r = -0.857, P = .014). Higher TL correlated with worse WC (r = 0.829, P = .042) and coach (r = 0.893, P = .007) ranking. This research in elite gymnasts indicated associations between decreased TST, augmented TL and inferior performance. Optimizing sleep and TL may therefore represent strategies to enhance performance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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). [Copyright &y& Elsevier]

Transcatheter arterial chemoembolization (TACE) offers a survival benefit to patients with intermediate hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes administration of doxorubicin-oil emulsion followed by gelatine sponge-conventional TACE. Recently, a drug-eluting bead (DC Bead) has been developed to enhance tumor drug delivery and reduce systemic availability. This randomized trial compares conventional TACE (cTACE) with TACE with DC Bead for the treatment of cirrhotic patients with HCC. Two hundred twelve patients with Child-Pugh A/B cirrhosis and large and/or multinodular, unresectable, N0, M0 HCCs were randomized to receive TACE with DC Bead loaded with doxorubicin or cTACE with doxorubicin. Randomization was stratified according to Child-Pugh status (A/B), performance status (ECOG 0/1), bilobar disease (yes/no), and prior curative treatment (yes/no). The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the cTACE group (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The hypothesis of superiority was not met (one-sided P = 0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P = 0.038) compared to cTACE. DC Bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P < 0.001) and a significantly lower rate of doxorubicin-related side effects (P = 0.0001). TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease. [ABSTRACT FROM AUTHOR]

Interferons control viral replication and the growth of some malignant tumors. Since systemic application may cause severe adverse effects, tissue-specific expression is an attractive alternative. Liver-directed interferon gene therapy offers promising applications such as chronic viral hepatitis B or C or hepatocellular carcinoma and thus needs testing in vivo in suitable animal models. We therefore used the Tet-On system to regulate gene expression in adenoviral vectors, and studied the effect of liver-specific and regulated interferon?expression in a mouse model of chronic hepatitis B virus (HBV) infection. In a first generation adenoviral vector, genes encoding for firefly luciferase and interferonsa,ßor?, respectively, were coexpressed under control of the bidirectional tetracycline-regulated promoter Ptetbi. Liver-specific promoters driving expression of the reverse tetracycline controlled transactivator ensured local expression in the livers of HBV transgenic mice. Following gene transfer, we demonstrated low background, tight regulation and a 1000-fold induction of gene expression by doxycycline. Both genes within the bidirectional transcription unit were expressed simultaneously, and in a liver-specific fashion in cell culture and in living mice. Doxycycline-dependent interferon?expression effectively controlled HBV replication in mice, but did not eliminate HBV transcripts. This system will help to study the effects of local cytokine expression in mouse disease models in detail.Gene Therapy (2005) 12, 668-677. doi:10.1038/sj.gt.3302449 Published online 13 January 2005 [ABSTRACT FROM AUTHOR]

Background: Idiopathic portal hypertension is a rare clinical syndrome which may be associated with a spectrum of histological lesions, including nodular regenerative hyperplasia and incomplete septal cirrhosis. Here, we report eight adult patients with idiopathic portal hypertension who experienced an unusually severe clinical evolution characterized by the development of progressive hepatic failure requiring orthotopic liver transplantation. Our aims are: (a) to stress the distinctive clinical presentation of these patients, (b) to describe their biological and histopathological features, and (c) to evaluate the results of orthotopic liver transplantation in this rare indication. Methods: Complete clinical charts and histological data were available in all patients. All patients were male. Their age at diagnosis ranged from 17 to 59 years. Complications of portal hypertension revealed the disease in all cases. Medical treatment was performed in all patients and portosystemic shunt in three. Results: The development of progressive hepatic failure led to the indication of liver transplantation after a delay ranging from 3 to 10 years. Explanted livers showed pure nodular regenerative hyperplasia in three patients and incomplete septal cirrhosis in five. Recovery was uneventful. All patients are alive, without recurrence of the disease. Conclusions: This report points to the existence of severe cases of idiopathic portal hypertension occurring without underlying or associated systemic disease and characterized by a poor clinical course and requiring liver transplantation. [ABSTRACT FROM AUTHOR]