Acute idiosyncratic liver injury after Cladribine treatment for multiple sclerosis: first case report and review on associated hepatic disorders.

In recent years, several disease-modifying therapies have been developed for the treatment of multiple sclerosis (MS). Cladribine transiently depletes B and T lymphocytes, with subsequent gradual cell recovery. No cases are reported in literature describing Cladribine drug-induced liver injury (DILI). We describe the case of a 19-year-old woman who developed acute idiosyncratic liver injury 12 days after treatment with Cladribine. Post-marketing adverse event reporting is of paramount importance to allow an early recognition and treatment. Moreover, evaluation of the physiopathological mechanism underlying drug-induced hepatic toxicity can provide clinicians with valuable instruments for prevention and treatment.

Prognostic factors of hepatic decompensation and hepatocellular carcinoma in patients with transfusion-acquired HCV infection.

AIMS: Aim of this study was to assess if host (immunogenetic traits, age, sex), exogenous (alcohol) or viral factors (viral type, past HBV infection) might affect the progression of chronic hepatitis C to liver decompensation or the development of HCC in a cohort of patients exposed to a single blood transfusion prior to the introduction of anti-HCV screening. METHODS: Two hundred and forty-eight patients with a history of a single exposure to blood or blood products prior to 1990 were retrospectively considered. Patients were devoid of other risk factors of liver disease or immunosuppression and naïve to antiviral therapies. Eight baseline variables were assessed: age at transfusion, sex, HBV core antibody, immunogenetic profile (DRB1*11, DRB1*1104, DRB1*07), HCV genotype and alcohol consumption. RESULTS: The follow-up was 22 (SD: 11) years. Sixty-eight patients (27%) progressed to hepatic decompensation over a median period of 22.5 years (IQR: 14-30) and 41 patients (16%) developed HCC over a median period of 31 years (IQR: 24-38). The cumulative incidence of liver failure was 0.4% (95% CI: 0.1-3.1), 4.9% (95% CI: 2.6-9.3) and 16.2% (95% CI: 10.4-24.7) at 10, 20 and 30 years after blood transfusion respectively. By univariate analysis, only age at transfusion was correlated with the risk of decompensation. Stratifying the age of transfusion by tertiles, the incidence of hepatic decompensation was 0.7% per year in patients transfused at ≤24 years of age as compared to 1.2% and 1.9% per year in those transfused at 25-35 and >36 years of age respectively (HR: 5.5, 95% CI: 2.78-10.7, P<0.001). The risk of HCC development was correlated by univariate analysis with age at transfusion (as continuous variable, HR: 1.12, 95% CI: 1.08-1.16 per year of age, P<0.001, >36 compared to ≤24 years, HR: 10.3, 95% CI: 3.9-26.9, P<0.001) and male sex (HR: 4.2, 95% CI: 1.7-10, P=0.001). Multivariate analysis confirmed age at transfusion and male sex as independent predictors of HCC development [HR: 1.12 per year (95% CI: 1.08-1.16), P<0.001 and HR: 5.4 (95% CI: 2.2-13.2), P<0.001 respectively]. CONCLUSIONS: In patients with transfusion-acquired HCV infection, age at transfusion affects the risk for hepatic decompensation. Age at transfusion and male sex are independent risk factors for HCC development.

Transarterial injection of (131)I-lipiodol, compared with chemoembolization, in the treatment of unresectable hepatocellular cancer.

UNLABELLED: Transarterial chemoembolization (TACE) improves survival in patients with hepatocellular carcinoma (HCC) in whom curative therapies are not suitable. The aim of this study was to assess survival differences in patients with hepatic cirrhosis and unresectable HCC treated by (131)I-lipiodol versus TACE or transarterial embolization (TAE). METHODS: A retrospective study was performed on a cohort of 124 patients undergoing treatment for unresectable HCC between 1997 and 2006. A total of 50 patients (44 men; mean age, 59 y) received (131)I-lipiodol (mean sessions per patient, 1.7), and 74 patients (63 men; mean age, 61 y) received TACE/TAE (mean sessions per patient, 1.8). Although no significant difference between the 2 treatment groups with respect to HCC size and clinical staging was observed, a higher proportion of patients with portal vein thrombosis (PVT) was treated with (131)I-lipiodol than with TACE/TAE (28% vs. 8%, P = 0.003). RESULTS: Actuarial survival was not significantly different between patients treated with (131)I-lipiodol and patients treated with TACE/TAE. Survival at 6 mo, 1 y, 2 y, and 3 y was 86%, 69%, 54%, and 45%, respectively, after (131)I-lipiodol, compared with 77%, 62%, 47%, and 43%, respectively, after TACE/TAE. However, patients with PVT survived a mean of 454 d after (131)I-lipiodol, compared with a mean of 171 d after TACE/TAE (P = 0.025). In addition, patients with more advanced disease (Barcelona Clinic Liver Cancer stage D) lived on average 363 d after (131)I-lipiodol, compared with 36 d after TACE/TAE (P = 0.014). CONCLUSION: In patients with unresectable HCC, there was no difference in survival between (131)I-lipiodol therapy and TACE/TAE treatment. However, in the patients with advanced clinical staging or PVT, there was a significant survival advantage for those treated with (131)I-lipiodol.

Efficacy of loco-regional ablation therapy of HCC in a population of liver transplanted patients.

BACKGROUND AND OBJECTIVE: Loco-ablation therapy (LAT) has become standard treatment for patients with HCC who are candidates for liver transplantation (LT). The aim of this study was: to evaluate if LAT was able to induce complete necrosis of tumour mass; to determine the tumour recurrence rate after LT and factors associated with recurrence. PATIENTS: The percentage and the distribution of necrosis in 116 HCC nodules of 61 patients with (26 patients) and without (35 patients) previous types of LAT were examined in explanted livers. RESULTS: Total necrosis was found only in 7% of treated nodules, and 42% of these showed absence of necrosis. The amount of necrosis was significantly related to the gross appearance of HCC: a single nodule with smaller adjacent satellite nodules showed a higher percentage of necrosis. No relation was found between the amount of necrosis and the type of LAT. Recurrence was observed in 11.5% and 8.5% of patients with and without previous LAT, respectively (P = ns). CONCLUSIONS: LAT very rarely induces complete necrosis; the amount of necrosis seems to depend on the growth pattern of the tumour and not on the type of previous LAT; the tumour size, measured at explant, is the only variable significantly related to recurrence.

Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies.

BACKGROUND: Chemoembolization (TACE) improves survival in cirrhotic patients with hepatocellular carcinoma (HCC). The optimal schedule, or whether embolization (TAE) alone gives the same survival advantage, is not known. PURPOSE: To evaluate whether specific patient characteristics and/or radiological transarterial techniques result in better outcomes. METHOD: A PubMed search was carried out for cohort and randomized trials (n = 175) testing transarterial therapies; meta-analysis was performed where appropriate. RESULTS: Anticancer drugs were used as sole agent in 75% of cases (double 15% and triple 6%): doxorubicin (36%), cisplatin (31%), epirubicin (12%), mitoxantrone (8%), mitomycin (8%), and SMANCS (5%). Embolizing agents used were: gelatin sponge particles (71%), polyvinyl alcohol (PVA) particles (8%), degradable starch microspheres (DSM) (4%), and embospheres (4%). Sessions per patient were 2.5 +/- 1.5 (interval: 2 months). Objective response was 40 +/- 20%; survival rates at 1, 2, 3, and 5 years were: 62 +/- 20%, 42 +/- 17%, 30 +/- 15%, and 19 +/- 16%, respectively, and survival time was 18 +/- 9.5 months. The post-TACE complications were: acute liver failure, 7.5% (range 0-49%); acute renal failure, 1.8% (0-13%); encephalopathy, 1.8% (0-16%); ascites, 8.3% (0-52%); upper gastrointestinal bleeding; 3% (0-22%); and hepatic or splenic abscess, 1.3% (0-2.5%). Treatment-related mortality was 2.4% (0-9.5%), mainly due to acute liver failure. Our meta-analysis of nine randomized controlled trials (RCTs) confirmed that TACE improves survival; but a meta-analysis of TACE versus TAE alone (3 RCTs, 412 patients) demonstrated no survival difference. CONCLUSIONS: No chemotherapeutic agent appears better than any other. There is no evidence for benefit with lipiodol. Gelatin sponge is the most used embolic agent, but PVA particles may be better. TAE appears as effective as TACE. New strategies to reduce the risk of post-TACE complications are required.

Treatment outcomes for hepatocellular carcinoma using chemoembolization in combination with other therapies.

BACKGROUND: Although transarterial chemoembolization (TACE) improves survival in patients with hepatocellular carcinoma (HCC), it is not known if TACE combined with other treatments is beneficial. AIM: To evaluate the evidence for improved outcomes in HCC with a multimodal treatment approach involving TACE. METHOD: PubMed search for all cohort and randomized trials (n=84) evaluating TACE combined with other therapies; meta-analysis performed where appropriate. RESULTS: A meta-analysis involving 4 RCTs showed a significant decrease in mortality favouring combination treatment (TACE plus percutaneous ablation) compared to monotherapy in patients with either small (<3cm) or large HCC nodules (>3cm) (OR, 0.534; 95% CI, 0.288-0.990; p=0.046). TACE combined with local radiotherapy improved survival in patients with tumour thrombosis of the portal vein in 7 non-randomized studies. Two RCTs and 13 non-randomized studies showed that TACE prior to hepatic resection does not improve survival nor tumour recurrence. Conversely, 2 RCTs and 5 comparative studies showed that transarterial injection of chemotherapeutic drugs mixed with lipiodol (TOCE) following hepatectomy confers survival benefit and less tumour recurrence. TACE before liver transplantation is safe and reduces drop-out rate from the waiting list, but there is no current evidence of improvement in subsequent survival or recurrence rate. CONCLUSIONS: A combined approach involving TACE and percutaneous ablation improves survival. Adjuvant TOCE improves outcome after hepatectomy. TACE is useful to control tumours burden while on the waiting list for OLT. Multimodal treatment seems to be the best way to optimize TACE outcomes in HCC.

Severe venoocclusive disease after liver transplantation treated with transjugular intrahepatic portosystemic shunt.

Venoocclusive disease (VOD) is due to hepatic sinusoidal lining injury leading to portal hypertension; its incidence after liver transplantation is about 2%. When severe, it does not respond to medical therapy and has a high mortality; retransplantation is the only therapeutic option. However, there are no detailed data regarding the use of transjugular intrahepatic portosystemic shunt for VOD after liver transplantation. We describe two patients who developed severe VOD after liver transplantation, failed defibrotide therapy, and were treated by transjugular intrahepatic portosystemic shunt (TIPS). The portal hypertension resolved completely and one had full histological recovery. We believe that TIPS should be attempted as it may resolve progressive portal hypertension and the hepatic congestion, while allowing the clinician time for listing for further liver transplantation if the patient fails to respond.

Liver transplantation and recurrent hepatocellular carcinoma: predictive value of nodule size in a retrospective and explant study.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major cause of post-LT death. METHODS: To assess which preoperative and postoperative variables were related to recurrence of HCC after LT in patients with cirrhosis and HCC, we evaluated 96 patients with cirrhosis (74 with known HCC and 22 with incidental HCC) who survived more than 1 month after LT. RESULTS: The median waiting list time was 36 days (range 1-370 days), and the median interval from detection to transplant was 180 days (range 14-1460 days). The size of largest nodule on imaging was strongly associated with recurrence (odds ratio 1.03; 95% confidence interval 0.99-1.06; P=0.064) when transplantation was performed for known HCC. Among postoperative variables, only the largest nodule diameter (independently of the number of smaller nodules) was multivariately associated with recurrence (odds ratio 1.05; 95% confidence interval 1.01-1.08; P=0.005). The best predictive cutoff was 35 mm in diameter, based on a receiver operating curve with 1-, 3-, and 5-year recurrence-free survival of 90%, 73%, and 49%, respectively, for patients with a nodule 35 mm in diameter or more compared with 96%, 93%, and 89% (P=0.0005), respectively, for patients with smaller nodules. CONCLUSIONS: In our cohort with a short waiting list time, only the largest nodule diameter, especially in the explant, predicted recurrence after LT independently of the number of nodules. New proposals for increasing the diameter of the largest nodule as a selection criteria for LT do not agree with our data, which on the contrary indicate the optimal nodule diameter should be 35 mm or less.

Liver transplantation and hepatitis C virus: systematic review of antiviral therapy.

Antiviral therapy for recurrent hepatitis C after liver transplantation is increasingly used. This systematic review presents both viral and histological response in three areas: pretransplant (5 studies/180 patients), preemptive therapy soon after transplant (10 studies/417 patients), and therapy for established disease (75 studies/2027 patients). There were only 16 randomized studies (543 patients). Significant dose reductions and drug stoppage rates occurred. The data on histological improvement and risk of rejection are conflicting. Even the best antiviral therapy (pegylated interferon/ribavirin) is neither easily used nor reasonably effective. The best strategy will be pretransplant treatment, most likely with newer agents.