Efficacy and Safety of Sorafenib After Liver Transplantation: Experience in Our Center.

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is increasing, with a consequent impact on survival. Here we report our experience with sorafenib to treat HCC recurrence after LT. PATIENTS AND METHODS: We undertook a retrospective cohort study of LT patients with recurrent HCC. RESULTS: The study included 12 patients with recurrent HCC after LT between January 2008 and March 2019; 9 were men and 3 women, with a median age of 58 years. Adverse effects were manageable in most patients with symptomatic treatment or with sorafenib dose adjustment. Stable disease was the best response and was achieved. Eight patients (66.7%) died during the study period, 5 (62.5%) due to tumor progression and 3 (37.5%) because of sepsis. The median survival time was 7.5 months.

Chest Wall Implantation Metastasis Caused by Percutaneous Interventional Procedure Appearing 12 Years After Liver Transplantation: A Case Report.

Percutaneous treatments (mainly radiofrequency ablation and ethanol injection) are modes of treatment for hepatocellular carcinoma. Seeding of malignant cells along the percutaneous tract is a very rare complication. We present a case of chest wall metastasis caused by radiofrequency ablation appearing years after liver transplantation.

Efficacy and Safety of Anti-TNF-α Agents in Inflammatory Bowel Disease After Liver Transplant: A Case Series.

BACKGROUND: Ulcerative colitis (UC) and Crohn disease (CD) can appear de novo or worsen after liver transplant. Our aim was to assess the efficacy and safety of anti-tumor necrosis-alpha (anti-TNF-α) agents after transplantation. METHODS: We reviewed the clinical database of our center searching for all liver transplant patients with inflammatory bowel disease who were treated with anti-TNF-α agents between 1997 and 2017. Clinical response was assessed from clinical activity indices 12 weeks after starting treatment. The median age of the 6 patients (3 women) was 37 years. Four patients were diagnosed before transplantation (2 UC and 2 CD), and in the other 2 the disease appeared de novo (1 UC and 1 CD). The indications for transplant were primary sclerosing cholangitis (n = 3), cryptogenic cirrhosis (n = 2), and hepatitis C virus cirrhosis (n = 1). RESULTS: Clinical response was seen in 3 of the 6 patients and, in the 3 cases for whom endoscopic data were available, no mucous healing was seen. The only adverse effects noted over a mean follow-up of 15 months were 1 cytomegalovirus infection and 1 severe infusion reaction to infliximab. No patients had recurrence of primary sclerosing cholangitis in the graft, and none of the patients died. CONCLUSION: Use of an anti-TNF-α agent in a liver transplant patient with inflammatory bowel disease may be an effective option, with an acceptable risk-benefit ratio. Further studies are required to confirm their use in this context.

Retransplant Due to Fulminant Hepatic Failure From Hepatitis E Virus: A Case Report.

Hepatitis E virus (HEV) usually causes self-limiting acute liver infections from fecal or oral transmission, though other routes of infection exist (vertical transmission, blood transfusion, zoonosis). It may give rise to fulminant hepatic failure in 1% of cases. Cases have recently been reported of chronic infection evolving to cirrhosis in immunosuppressed patients, such as those with a liver or kidney transplant. Nonetheless, development of acute liver failure in these patients is exceptional, with few cases published. We present a case of acute liver failure due to HEV in a liver transplant patient who required a liver retransplant 9 years after receiving the original transplant.

Efficacy and safety of monotherapy with mycophenolate mofetil in liver transplantation.

AIM: To analyze the efficacy and safety of mycophenolate mofetil (MMF) as monotherapy in liver transplant patients who have adverse effects associated with calcineurin inhibitors (CNIs). PATIENTS AND METHODS: Seventeen patients, 13 men and four women, mean age 62 years, who received a liver transplant between 1998 and 2003 and initial immunosuppressive therapy with CNIs (10 tacrolimus and seven cyclosporine), were converted to monotherapy with MMF due to adverse events associated with CNIs: chronic renal failure in 16 patients (four with diabetes mellitus and seven with hypertension) and neurotoxicity in one patient. The mean time between transplant and starting monotherapy was 32 months (range: 18 to 70) and the mean follow-up time on monotherapy was 20 months (range: 8 to 39). MMF was introduced gradually at the same time as the CNIs were reduced. RESULTS: There was a progressive decrease in creatinine during the initial months. Compared with baseline levels, the differences at 3 and 6 months of monotherapy were significant (P < .001), remaining so throughout the follow-up period. Renal function improved in 15 of 17 patients (88%) and normalized in 10 of 17 (60%). The patient with neurotoxicity due to CNI improved. One patient (6%) had moderate rejection that was corrected after reintroducing tacrolimus. In two patients it was necessary to suspend MMF, one due to gastrointestinal intolerance and the other due to severe myelotoxicity and Pneumocystis jiroveci infection. Other, minor adverse events were corrected by adjusting the dose: one herpes zoster, two diarrhea, and two anemia. CONCLUSIONS: Monotherapy with MMF efficiently and safely corrected renal dysfunction associated with CNIs, with few side effects and a low incidence of rejection.

Endoscopic Management of Post-Liver Transplantation Biliary Strictures With the Use of Fully Covered Metallic Stents.

OBJECTIVE: The aim of this work was to evaluate the safety and efficacy of a fully covered self-expandable metal stent (FCSEMS) in the treatment of post-liver transplantation biliary strictures. METHODS: From October 2009 to October 2014, 44 patients with post-liver transplantation biliary stenosis were treated with the use of endoscopic retrograde cholangiography and placement of FCSEMS after informed consent. The FCSEMS was scheduled to remain in situ for 3-6 months. Patients were followed at regular intervals to evaluate for symptoms and liver function tests. Technical success, complications, and patient outcome were analyzed. RESULTS: All of the strictures were anastomotic, 52% having occurred within the 1st year following the transplantation. Placement of the FCSEMS was possible on the 1st attempt in 54% of patients. Stricture resolution at the time of stent removal was seen in 100% of the cases. During an average follow-up of 27.83 ± 18.3 months after stent removal, stenosis recurred in 9 out of 41 patients (21.9%). The average time of recurrence was 11.78 ± 13.3 months. In all of these cases, the recurrence was resolved by means of placement of another FCSEMS. In 4 cases, the recurrence was associated with a migration of the prosthesis, partial in 2 cases and total in 2 cases. Stent migration occurred in a total of 17 of the 41 patients (41.4%), in 13 of the 32 (40.6%) who had no recurrence of stenosis and in 4 of the 9 (44.4%) of those who experienced recurrence. The average numbers of endoscopic retrograde cholangiography studies required per patient were 2.8 in those with no recurrence and 3.3 in those with recurrence. No death was associated with the process. CONCLUSIONS: FCSEMS is a safe effective alternative to plastic stents in the treatment of post-transplantation biliary strictures, resulting in a lower risk of complications and better patient acceptance.

Everolimus plus mycophenolate mofetil as initial immunosuppression in liver transplantation.

BACKGROUND: The purpose of this study was to assess the efficacy and safety of a de novo immunosuppressive regimen with everolimus (EVL) plus mycophenolate mofetil (MMF) without calcineurin inhibitors (CNI) for liver transplantation. The secondary purpose was to compare the renal function with a control group of patients treated with tacrolimus plus MMF. METHODS: Sixteen male and 4 female liver transplant patients received immunosuppression with EVL plus MMF without CNI, with induction with steroids and 16 with basiliximab also. In 10 cases it was indicated as induction immunosuppression without CNI as prevention against nephrotoxicity and neurotoxicity or recurrence of hepatocarcinoma in predisposed patients and in another 10 after withdrawing CNI during the immediate post-transplant period, before hospital discharge, as the result of toxicity, mainly nephrotoxicity and neurotoxicity or the presence of hepatocarcinoma with a high risk of recurrence. A control group comprising 31 patients taking tacrolimus plus MMF was included to compare the renal function. RESULTS: The mean follow-up time was 24 months. One patient had a recurrence of hepatocarcinoma at 8 months after transplant. The cases of nephrotoxicity and neurotoxicity resolved favorably. There were 7 rejections (35%); 2 evolved to chronic rejection with both needing retransplantation, 2 resolved with dose adjustment, and 3 required conversion to CNI. The side effects were hyperlipidemia (25%), wound dehiscence (10%), lymphedema (10%), cytomegalovirus infection (25%), myelotoxicity (25%) and proteinuria >1 g in 1 case (5%). No differences were found in renal function between the two groups. CONCLUSIONS: This regimen was proven to be efficient to prevent and treat nephrotoxicity and neurotoxicity with an acceptable tolerability profile. However, the high associated rejection rate indicates that great caution is required in its use during the immediate post-transplant period. It is advisable to associate the regimen with low doses of CNI and to have agile methods available to monitor EVL to enable rapid dose adjustment.

Distinct phenotype of hepatotoxicity associated with illicit use of anabolic androgenic steroids.

BACKGROUND: We have observed an increase in hepatotoxicity (DILI) reporting related to the use of anabolic androgenic steroids (AAS) for bodybuilding. AIM: To characterise phenotype presentation, outcome and severity of AAS DILI. METHODS: Data on 25 cases of AAS DILI reported to the Spanish (20) and Latin-American (5) DILI Registries were collated and compared with previously published cases. RESULTS: AAS DILI increased from representing less than 1% of the total cases in the Spanish DILI Registry in the period 2001-2009 to 8% in 2010-2013. Young men (mean age 32 years), requiring hospitalisation, hepatocellular injury and jaundice were predominating features among the AAS cases. AAS DILI caused significantly higher bilirubin values independent of type of damage when compared to other drug classes (P = 0.001). Furthermore, the cholestatic AAS cases presented significantly higher mean peak bilirubin (P = 0.029) and serum creatinine values (P = 0.0002), compared to the hepatocellular cases. In a logistic regression model, the interaction between peak bilirubin values and cholestatic damage was associated with the development of AAS-induced acute kidney impairment (AKI) [OR 1.26 (95% CI: 1.035-1.526); P = 0.021], with 21.5 ×ULN being the best bilirubin cut-off point for predicting AKI risk (AUCROC 0.92). No fatalities occurred. CONCLUSIONS: Illicit recreational AAS use is a growing cause of reported DILI that can lead to severe hepatic and renal injury. AAS DILI is associated with a distinct phenotype, characterised by considerable bilirubin elevations independent of type of damage. Although hepatocellular injury predominates, acute kidney injury develops in cholestatic cases with pronounced jaundice.

Analysis of the recurrence of hepatitis C virus after liver transplantation: results of the Andalusian liver registry.

OBJECTIVE: This study analyzed the factors related to recurrence of hepatitis C virus (HCV) among orthotopic liver transplantation (OLT) patients. PATIENTS AND METHODS: We undertook a multicenter, prospective, observational study of OLT patients transplanted due to HCV at four Andalusian transplantation centers from 2005 to 2007. Patients were excluded if their survival was less than 1 month. The analysis included 110 pre-, peri-, and posttransplant variables that could affect HCV recurrence. We also examined the influence of cardiovascular risk factors and immunosuppression on HCV. RESULTS: Among 121 HCV patients, 83 (69%) experienced a histologically significant recurrence of HCV, including 13 (16%) who died compared with 5 of 38 (13%) who did not show a severe recurrence of HCV (P = .3). The mean follow-up was 44 months (range, 4 to 64 months). The mean time to appearance of the relapse was 9 months (range, 1 to 40 months) with no differences according to the type of immunosuppression. Of all study variables, donor age (> 52 years) showed a trend for greater recurrence (P = .1). The use of powerful immunosuppression (three or more drugs), either as induction or as sustained therapy, during the first posttransplantation year was significantly associated with a greater relapse rate (P < .01), albeit with no significant difference according to the type of calcineurin inhibitor. Mycophenolate mofetil was not associated with a greater posttransplantation viral load or earlier relapse, although its use in multiple immunosuppression schedules was associated with a greater relapse rate (P < .01). Survival of patients with recurrent HCV was reduced, although not significantly. Multivariate analysis showed a 4.4 times greater risk for developing de novo diabetes mellitus (DM) among patients with a severe relapse of HCV. CONCLUSIONS: There was an important trend toward a greater recurrence rate of HCV among patients who received powerful immunosuppression protocols, particularly during the first 12 months. Special attention should be given to the risk for de novo DM among HCV-positive patients.

Efficacy and safety of entecavir and/or tenofovir for prophylaxis and treatment of hepatitis B recurrence post-liver transplant.

AIMS: To establish the efficacy and safety of entecavir (ETV) and/or tenofovir (TDF) in the treatment and prevention of hepatitis B virus (HBV) recurrence after liver transplantation. PATIENTS AND METHODS: Eight patients (four men) received treatment with ETV and/or TDF after liver transplantation as prophylaxis for HBV recurrence or as posttransplant treatment of HBV. Four liver transplants were in patients with HBV-associated cirrhosis who had received prior nucleos(t)ide analogue treatment until HBV DNA became undetectable. After transplantation, two of these four were treated with ETV + TDF and the other two with just TDF. All received intramuscular hepatitis B immunoglobulins. The reasons for the other four liver transplants were primary biliary cirrhosis in two cases, alcoholic cirrhosis, and hepatitis C virus. Two of the patients were donor anti-HBcAb-positive/recipient anti-HBcAb-negative. They received no anti-HBV prophylaxis so they had a recurrence of HBV. These four patients required treatment with ETV+TDF for the HBV DNA to become negative. RESULTS: The mean age was 60 (39-67) years. The mean follow-up was 9.5 (3-20) months. The mean follow-up of the patients who received prophylaxis was 8.2 (3-19) months. These had no HBV recurrence. The mean follow-up of the patients who received treatment for HBV recurrence was 12 (3-19) months. ETV combined with TDF was necessary for the HBV DNA to become undetectable because this was not possible using different nucleos(t)ide analogues. There were no significant adverse effects from these drugs and no alteration of renal function during the follow-up period. CONCLUSIONS: Therapy with ETV and/or TDF seems to be efficient and safe when used in the prophylaxis and treatment of HBV recurrence after liver transplantation. They are well tolerated and seem to have no interactions with immunosuppressive medication.

Influence of mycophenolate mofetil on preservation of kidney function in liver transplant patients.

BACKGROUND: There are numerous studies on the effect of immunosuppressive therapy with mycophenolate mofetil (MMF) on preservation of kidney function in liver transplant (OLT) patients with chronic kidney damage. However, we have noted few studies that evaluate the role of this drug prescribed from induction on kidney function. PATIENTS AND METHODS: This prospective observational multicenter study included 296 OLT performed from 2005 to 2007. The collected variables were; gender, and age, Child-Pugh stage, Model for End-Stage Liver Disease (MELD) score, transplant indication, induction immunosuppressive therapy, and baseline and 1 year posttransplant values of creatinine and glomerular filtration rate. Patients were classified into 4 groups: group 1 received MMF from induction; group 2 was never treated with MMF; group 3 started MMF in the first month posttransplant, and group 4 started MMF therapy in the third month posttransplant. We used Wilcoxon and Mann-Whitney U statistical tests. RESULTS: There was a difference of 0.18 mg/dL in baseline creatinine values between groups 1 and 2 (P < .01). However, although patients who consistently had MMF in their treatment started with worse creatinine values, they were able to maintain them within normal ranges at 12 months. In contrast, patients in group 2 showed a significant worsening of 0.28 mg/dL in the first month that persisted throughout the study. Group 3 displayed worse baseline creatinine values than group 2 (P < .05), and also suffered an increase of 0.29 mg/dL (P < .01) versus baseline at 1 month. When MMF was added to their immunosuppressive therapy, the creatinine values reduced versus 1 month by 0.18 mg/dL (P < .05). Creatinine values remained stable at the other study assessments. Group 4 showed a normal creatinine value at baseline, but were altered at 1 and 3 months (P < .01), with increases versus baseline of 0.46 and 0.35 mg/dL, respectively. However, when MMF was introduced kidney function was restored and maintained over the study. CONCLUSION: Early introduction of MMF improved creatinine values among patients with impaired kidney function, maintaining them at stable levels. Furthermore, patients with altered creatinine values at baseline did not worsen their kidney function if they receive MMF from induction.

Hepatitis C virus recurrence after liver transplantation: analysis of factors related to sustained viral response.

OBJECTIVES: To determine the efficacy and safety of pegylated interferon (peg-IFN) plus ribavirin to treat hepatitis C virus (HCV) recurrence, analyzing possible factors associated with sustained viral responses (SVR). PATIENTS AND METHODS: Forty-one patients (25 men and 16 women) of overall mean age of 50 years (range, 33-60) with recurrent HCV were treated with peg-IFN plus ribavirin including 33 (80%) subjects displayed genotype 1. The following variables were analyzed: gender, donor and recipient ages, immunosuppressant, genotype, treatment duration, early viral response (EVR), pretreatment viral load, degree of fibrosis, levels of alanine aminotransferase and gamma-glutamyltransferase (IU/L), time since liver transplantation (OLT), use of stimulating factors (epoetin and granulocyte colony stimulating factor [G-CSF]) and side effects, and their association with SVR. The time from OLT to the start of treatment was 29 months (range, 6-90). Seventy-one percent of patients received cyclosporine and 29% tacrolimus. RESULTS: The mean treatment duration was 31 (range, 4-72) months with an EVR achieved in 12/38 (31.5%) of patients and a SVR in 16/41 (39%). Treatment was discontinued in 23 patients due to side effects. Epoetin was necessary in 29% and G-CSF in 10%. There were 3 cases of rejection (1 mild and 2 severe culminating in death). On univariate analysis genotype non-1B (P < .02), pretherapy RNA (P < .02), complete treatment, and EVR (P < .005) were the only variables associated with SVR. The mean donor age of 43 years showed no statistical significance. CONCLUSION: Therapy with peg-IFN plus ribavirin achieves an acceptable SVR, although not entirely free from severe side effects. Ensuring completion of the full treatment course is fundamental to achieve SVR.

[Safety and efficacy of the MARS therapy applied by continuous renal replacement therapy (CRRT) monitors]. / Seguridad y eficacia de la terapia MARS aplicada mediante monitores de TCRR.

OBJECTIVE: Analyze the utility and safety of MARS therapy applied with the CRRT monitor. DESIGN: Prospective study of cohorts. SCOPE: Polyvalent ICU in tertiary university hospital with hepatic transplantation program. PATIENTS: Thirty one patients: 9 (22.6%) with acute liver failure (ALF) (1 hepatic surgery, 1 primary graft failure, 7 other causes) and 22 (71%) with acute-on-chronic failure (AoCLF). INTERVENTIONS: For the treatment, the patients with ALF are maintained in the ICU but those with AoCLF are admitted for the performance of the different sessions, that are programmed for a duration of at least 15 hours in AoCLF and in ALF are maintained continuously, changing the circuit every 24 hours. VARIABLES OF INTEREST: Metabolic control and complications registered in 75 sessions on 31 patients. RESULTS: Urea decrease was 33.5 (29-38%), creatinine 36 (31-41%), total bilirubin 29 (25-33%) and direct bilirubin 34 (30-38%). Clearance was slower, but sustained, after the first 4 hours of each session both for urea (p<0.001) as well as for bilirubin (p<0.05). The hemodynamic parameters improved and the hematological ones were not altered. We detected decrease in platelets (131 to 120x109/L, p<0.01). In 95 of the sessions in which heparin was used and in 6% where epoprostenol was used, we observed mild bleeding. We cultured albumin of the circuit at the end of the session in 50 occasions and only obtained growth in 3 cases (6%) (2 Staphylococcus epidermidis, 1 S. haemolyticus) without signs of contamination in the patients. CONCLUSIONS: The MARS system applied by CRRT monitors provide adequate bilirubin clearance percentages and is safe, even in serious patients. Prolongation of the duration of the sessions was not accompanied by an increase in the risk of infection secondary to the albumin contamination.