Cristina Morelli

Sleep disturbance and daytime sleepiness in patients with cirrhosis: a case control study

Sleep disturbance and excessive daytime sleepiness have been reported in patients with hepatic cirrhosis. The objective of this study was to evaluate daytime somnolence and sleep complaints in a group of 178 patients with cirrhosis compared to a control group. Sleep features and excessive daytime sleepiness were evaluated by the Basic Nordic Sleep Questionnaire (BNSQ) and the Epworth Sleepiness Scale (ESS). We collected clinical and laboratory data, neurological assessment and EEG recordings in cirrhotic patients. Patients with cirrhosis complained of more daytime sleepiness (p<0.005), sleeping badly at least three times a week (p<0.005), difficulties falling asleep (p<0.01) and frequent nocturnal awakening (p<0.005) than controls. We found a poor correlation between sleep disorders and clinical or laboratory parameters. Our results confirm previous literature reports suggesting a high prevalence of sleep disturbance in patients with cirrhosis. Insomnia and daytime sleepiness are the main complaints. Sleep disorders are probably a multifactorial phenomenon.

Liver transplantations with donors aged 60 years and above: the low liver damage strategy

According to transplant registries, grafts from elderly donors have lower survival rates. During 1999–2005, we evaluated the outcomes of 89 patients who received a liver from a donor aged ≥ 60 years and managed with the low liver‐damage strategy (LLDS), based on the preoperative donor liver biopsy and the shortest possible ischemia time (group D ≥ 60‐LLDS). Group D ≥ 60‐LLDS was compared with 198 matched recipients, whose grafts were not managed with this strategy (89 donors < 60 years, group D < 60‐no‐LLDS and 89 donors aged ≥60 years, group D ≥ 60‐no‐LLDS). In the donors proposed from the age group of ≥60 years, the number of donors rejected decreased during the study period and the LLDS was found to be responsible for this in a significant manner (47% vs. 60%, respectively P < 0.01). Among the recipients transplanted, the clinical features (age, gender, viral infection, child and model for end‐stage liver disease score) were comparable among groups, but group D ≥ 60‐LLDS had a lower mean ischemia time: 415 ± 106 min vs. 465 ± 111 (D < 60‐no‐LLDS), P < 0.05 and vs. 476 ± 94 (D ≥ 60‐no‐LLDS), P < 0.05. After a median follow‐up of 3 years, the 1‐ and 3‐year graft survival rates of group D ≥ 60‐LLDS (84% and 76%) were comparable with group D < 60‐no‐LLDS (89% and 76%) and were significantly higher than group D ≥ 60‐no‐LLDS (71% and 54%), P < 0.005. In conclusion, the LLDS optimized the use of livers from elderly donors.

Tissue hepatitis C virus RNA quantification and protein expression help identify early hepatitis C virus recurrence after liver transplantation

We compared tissue hepatitis C virus (HCV) RNA polymerase chain reaction quantification and HCV immunohistochemistry (IHC) to histology in biopsy tissues in order to differentiate between acute rejection and HCV hepatitis recurrence early after orthotopic liver transplantation (OLT). We analyzed the first biopsy performed because of alteration of serum aminotransferases in 65 consecutive OLT patients with HCV genotype 1b. In the histological analysis, we quantified the portal tracts, Councilman bodies, Councilman body/portal tract (CP) ratio, steatosis, and Knodell and Ishak scores. The 52 patients (80%) with histological HCV recurrence [recurrence‐positive (Rec+)] were separated from the 6 (9%) with acute rejection and the 7 (11%) with undetermined pathological features [recurrence‐negative (Rec−)]. HCV RNA strongly correlated with HCV IHC, regardless of the histological diagnosis (P < 0.001). Both HCV RNA and HCV IHC were significantly associated with CP ratio (P = 0.041 and P = 0.008). No statistical correlation was found between HCV RNA, HCV IHC, and the other histopathologic features or the hepatitis scores. HCV RNA, HCV IHC, and CP ratio were the only variables able to discriminate between Rec+ and Rec− patients (Mann‐Whitney test P < 0.001, P < 0.001, P = 0.014). In conclusion, a combined evaluation of histology, tissue HCV RNA, and HCV IHC significantly discriminated between OLT patients with or without HCV recurrence. Liver Transpl 14:313–320, 2008.

Prevention of hepatitis C recurrence by bridging sofosbuvir/ribavirin from pre to post liver transplant: a real life strategy

Hepatitis C virus (HCV) re‐infection following liver transplant (LT) is associated with reduced graft and patient survival. Before transplant, Sofosbuvir/Ribavirin (SOF/R) treatment prevents recurrent HCV in 96% of those patients achieving viral suppression for at least 4 weeks before transplant. We evaluated whether a bridging SOF‐regimen from pre‐ to post‐transplant is safe and effective to prevent HCV recurrence in those patients with less than 4 weeks of HCV‐RNA undetectability at the time of transplant.

Recipient female gender is a risk factor for graft loss after liver transplantation for chronic hepatitis C: Evidence from the prospective Liver Match cohort.

BACKGROUND Female gender has been reported to be a risk factor for graft loss after liver transplantation for hepatitis C virus (HCV)-related cirrhosis but evidence is limited to retrospective studies. AIMS To investigate the impact of recipient gender and donor/recipient gender mismatch on graft outcome. METHODS We performed a survival analysis of a cohort of 1530 first adult transplants enrolled consecutively in Italy between 2007 and 2009 and followed prospectively. After excluding possible confounding factors (fulminant hepatitis, human immunodeficiency virus co-infection, non-viremic anti-HCV positive subjects), a total of 1394 transplant recipients (604 HCV-positive and 790 HCV-negative) were included. RESULTS Five-year graft survival was significantly reduced in HCV-positive patients (64% vs 76%, p=0.0002); Cox analysis identified recipient female gender (HR=1.44, 95% CI 1.03-2.00, p=0.0319), Mayo clinic End stage Liver Disease score (every 10 units, HR=1.25, 95% CI 1.03-1.50; p=0.022), portal thrombosis (HR=2.40, 95% CI 1.20-4.79, p=0.0134) and donor age (every 10 years, HR=1.14, 95% CI 1.05-1.24, p=0.0024) as independent determinants of graft loss. All additional mortality observed among female recipients was attributable to severe HCV recurrence. CONCLUSIONS This study unequivocally shows that recipient female gender unfavourably affects the outcome of HCV-infected liver grafts.

Model for End-Stage Liver Disease (MELD) System to Allocate and to Share Livers: Experience of Two Italian Centers

BACKGROUND The use of the Model for End-stage Liver Disease (MELD) score to prioritize patients on liver waiting lists and to share organs among centers was effective according to US data, but few reports are available in Europe. MATERIALS AND METHODS We evaluated the outcome of 887 patients listed between April 2004 and July 2006 in a common list by two transplant centers (University of Bologna [BO] and University of Modena [MO] ordered according to the MELD system. Patients with hepatocellular carcinoma had a score calculated according to their real MELD, tumor stage, and waiting time. RESULTS Five hundred eighty-six (67%) patients were listed from BO and 291 (33%) from MO. The clinical features of recipients (sex, age, blood group, and real MELD) were comparable between centers. The number of liver transplantations performed was 307, and 273 (89%) recipients had a calculated MELD >or=20. Liver transplantations were equally distributed according to the number of patients listed: 215 out of 586 (36.7%) for BO and 92 out of 291 (31.6%) for MO. The median real MELD of patients transplanted was 20, and 246 out of 307 (80.1%) grafts transplanted were functioning. The dropouts from the list were 124 (14%), and 87 (70%) of these patients had a calculated MELD >or=20. CONCLUSION The MELD system was effective to share livers among the two Italian centers. According to this policy, livers were allocated to the recipients with the highest probability of dropout and who had a satisfactory survival after liver transplantation.

Induction Therapy With Alemtuzumab (Campath) in Combined Liver-Kidney Transplantation: University of Bologna Experience

BACKGROUND Combined liver-kidney transplantation (LKT) is considered to be a safe procedure, but the appropriate immunosuppressive regimen is unclear. PATIENTS AND METHODS Between January 1997 and October 2011, 55 patients were listed for LKT: 45 (82%) were effectively transplanted, 5 (9.2%) died whereon here the waiting list, 3 (5.5%) temporarily out of waiting list, 1 (1.8%) was on waiting list and 1 (1.8%) refused LKT. Five LKTs treated with cyclosporine (CyA) were excluded from the analysis. Mean recipient age was 50.32 ± 10.32 years (14-65), MELD score at time of LKT was 19.22 ± 4.69 (8-29), mean waiting list time was 8.14 ± 9.50 months (0.1-35.76), and follow-up, 4.09 ± 3.02 years (0.01-10.41). Main indications for LKT were policystic disease (n = 15; 37%), hepatitis virus C (HCV)-related cirrhosis (n = 9; 22%) metabolic disease (n = 5; 13%), hepatitis virus B (HBV) cirrhosis (n = 4; 10%), alcoholic cirrhosis (n = 4; 10%), and cholestatic disease (n = 3; 8%). Immunosuppressive regimen was based on tacrolimus and steroids in 40 cases with induction therapy with alemtuzumab (Campath; 0.3 mg/kg) in 13 of 40 instances cases administered on day 0 and day 7. RESULTS Postoperative mortality was 2.5%. Acute cellular rejection episodes were biopsy-proven in 2 (5%) cases, post-LKT infections developed in 17 cases (42.5%), and de novo cancer developed in 3 (7.5%) cases. Similar 5-year overall survivals were obtained irrespective of the LKT indication: 100% in cholestatic and alcoholic cirrhosis patients, 86% in policystic disease, 75% in metabolic disease and HBV patients, and 66% in HCV cirrhosis. Overall survivals for the alemtuzumab vs without-induction therapy groups at 1, 3, and 5-years were 100%, 85.7%, and 85.7% vs 76%, 76%, and 70%, respectively (P = .04). CONCLUSION An immunosuppressive regimen based on tacrolimus and steroids with induction therapy with alemtuzumab was safe, with excellent long-term results for combined LKT.

Combined Kidney-Liver, Heart-Liver, and Kidney-Pancreas Transplantations from a Single Deceased Donor

Splitting the liver for two adults to increase the donor pool is still a debated issue, especially for combined organ transplantation. We described a case of liver-splitting procedure for two adults, which was successful even in the presence of combined organ transplantation. Three adult combined organ transplantations from one deceased donor were performed, with, use of split liver grafts in two patients: a combined heart-right split liver, a left kidney-left split liver, and a right kidney-pancreas transplantation. Despite a not perfect match between the graft type and recipient, the prevention of small-for-size syndrome by ligature of the splenic artery, and/or hemiportocaval shunt in the patient receiving the left split liver, and the maximal reduction of ischemia time were the main factors contributing to the success of the procedure. This is the first report of combined heart and split liver in two adults which may suggest new strategies for organ transplantations.

Delisting HCV-infected liver transplant candidates who improved after viral eradication: Outcome 2 years after delisting

Treating patients with decompensated cirrhosis with direct‐acting antiviral (DAA) therapy while on the waiting list for liver transplantation results in substantial improvement of liver function allowing 1 in 4 patients to be removed from the waiting list or delisted, as reported in a previous study promoted by the European Liver and Intestine Transplant Association (ELITA). The aim of this study was to report on clinical outcomes of delisted patients, including mortality risk, hepatocellular carcinoma development and clinical decompensation requiring relisting.

Impact of DAAs on liver transplantation: Major effects on the evolution of indications and results. An ELITA study based on the ELTR registry

BACKGROUND & AIMS Direct-acting antivirals (DAAs) have dramatically improved the outcome of patients with hepatitis C virus (HCV) infection including those with decompensated cirrhosis (DC). We analyzed the evolution of indications and results of liver transplantation (LT) in the past 10 years in Europe, focusing on the changes induced by the advent of DAAs. METHODS This is a cohort study based on data from the European Liver Transplant Registry (ELTR). Data of adult LTs performed between January 2007 to June 2017 for HCV, hepatitis B virus (HBV), alcohol (EtOH) and non-alcoholic steatohepatitis (NASH) were analyzed. The period was divided into different eras: interferon (IFN/RBV; 2007-2010), protease inhibitor (PI; 2011-2013) and second generation DAA (DAA; 2014-June 2017). RESULTS Out of a total number of 60,527 LTs, 36,382 were performed in patients with HCV, HBV, EtOH and NASH. The percentage of LTs due to HCV-related liver disease varied significantly over time (p <0.0001), decreasing from 22.8% in the IFN/RBV era to 17.4% in the DAA era, while those performed for NASH increased significantly (p <0.0001). In the DAA era, the percentage of LTs for HCV decreased significantly (p <0.0001) from 21.1% (first semester 2014) to 10.6% (first semester 2017). This decline was more evident in patients with DC (HCV-DC, -58.0%) than in those with hepatocellular carcinoma (HCC) associated with HCV (HCV-HCC, -41.2%). Conversely, three-year survival of LT recipients with HCV-related liver disease improved from 65.1% in the IFN/RBV era to 76.9% in the DAA era, and is now comparable to the survival of recipients with HBV infection (p = 0.3807). CONCLUSIONS In Europe, the number of LTs due to HCV infection is rapidly declining for both HCV-DC and HCV-HCC indications and post-LT survival has dramatically improved over the last three years. This is the first comprehensive study of the overall impact of DAA treatment for HCV on liver transplantation in Europe. LAY SUMMARY After the advent of direct-acting antivirals in 2014, a dramatic decline was observed in the number of liver transplants performed both in patients with decompensated cirrhosis due to hepatitis C virus (HCV), minus 60%, and in those with hepatocellular carcinoma associated with HCV, minus 41%. Furthermore, this is the first large-scale study demonstrating that the survival of liver transplant recipients with HCV-related liver disease has dramatically improved over the last three years and is now comparable to the survival of recipients with hepatitis B virus infection. The reduction in HCV-related indications for LT means that there is a greater availability of livers, at least 600 every year, which can be allocated to patients with indications other than HCV.