Further decompensation in cirrhosis: Results of a large multicenter cohort study supporting Baveno VII statements.

BACKGROUND AND AIMS: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis. APPROACH AND RESULTS: Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and <1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23-1.71) ( p <0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999. CONCLUSIONS: In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis.

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

BACKGROUND & AIMS: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. METHODS: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. RESULTS: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. CONCLUSIONS: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. LAY SUMMARY: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

Adipopenia Is the Rapid Screening Tool that Best Predicts Mortality in Patients with Decompensated Cirrhosis: Results of a Prospective Study.

BACKGROUND AND AIMS: Patients with liver cirrhosis (LC) often have malnutrition (MN), which can be associated with decompensation, infection, and death. The aims were to determine: the prevalence of MN in patients with LC and ascites, its impact on mortality, and the relationship between MN and spontaneous bacterial peritonitis (SBP). METHODS: Nutritional status (NS) was analysed in cirrhotic patients, experiencing their first episode of ascites, who were consecutively admitted at two clinical liver centres between November 2014 and October 2016. The participants underwent diagnostic paracentesis and were followed up to assess their outcomes. RESULTS: 110 participants underwent NS assessment in addition to routine clinical procedures. The prevalence of MN was 30.9% according to corrected body mass index, 67.3% according to upper mid-arm muscle area (UMA) and 40% according to upper mid-arm fat area (UFA). The percentages of the participants remaining alive were 68.1% at 3 months, 59.3% at 6 months, 45.1% at 12 months and 24.2% at the end of the study. Univariate analysis showed that SBP, model for end-stage liver disease (MELD), UFA, UMA and age were significantly associated with mortality. Multivariate analysis showed that only SBP, MELD and UFA (hazard ratio 2.2) were independently associated with mortality. There was a correlation between adipopenia, but not sarcopenia, and SBP. CONCLUSIONS: Adipopenia, as assessed by UFA, was present in 40% of the cirrhotic patients, and it was independently associated with mortality.

Impact of Diabetes on Outcomes of Sorafenib Therapy for Hepatocellular Carcinoma.

BACKGROUND: Patients with diabetes are at increased risk of developing hepatocellular carcinoma (HCC) and have a poorer prognosis as compared to non-diabetics when HCC occurs. Diabetics with non-HCC cancers are at higher risk of toxicity related to systemic therapy, but data on HCC are lacking. OBJECTIVE: The aim of this study was to evaluate safety and effectiveness of sorafenib in HCC patients according to the presence/absence of diabetes. PATIENTS AND METHODS: From October 2008 to June 2014, 313 patients with HCC treated with sorafenib were enrolled. The patients were staged according to the BCLC system. Treatment response was evaluated according to the mRECIST criteria. The main evaluated outcomes were the overall survival and the safety in the two groups. RESULTS: Patients were divided in two groups: 80 diabetics (DIAB) and 233 nondiabetics (nDIAB). The median treatment duration was 4 months in DIAB and 3 months in nDIAB. Main adverse events occurred with comparable frequency in both groups, with the exception of rash, that was more frequent among DIAB than in nDIAB: 27.5 % vs 17.6 % (P = .047). The median overall survival was 9 months in nDIAB and 10 months in DIAB group (P = .535). Median time-to-progression (TTP) was longer the in DIAB than the nDIAB group (P = .038). CONCLUSIONS: Sorafenib was as safe as effective in DIAB and in nDIAB patients. The longer TTP observed among DIAB than in nDIAB patients might suggest a better anticancer effect of sorafenib in patients with diabetes.

Sorafenib off-target effects predict outcomes in patients treated for hepatocellular carcinoma.

AIM: Sorafenib is the standard of care in advanced hepatocellular carcinoma. This study was aimed to identify clinical parameters that may predict survival in these patients. MATERIALS & METHODS: In this observational study, a training (226 patients) and validation cohorts (54 patients) were analyzed for evaluating pretreatment and on-treatment parameters. RESULTS: At multivariate analysis, only on-treatment variables (skin toxicity, diarrhea and arterial hypertension - sorafenib off-target effects), alphafetoprotein and radiological responses predicted survival. Using the occurrence of off-target effects, a prognostic index able to distinguish three groups of patients with different survival was constructed and externally validated. CONCLUSION: In hepatocellular carcinoma patients, on-treatment variables are the best predictors of survival. Among these, sorafenib off-target effects may be the most useful indicators for prognostication in field practice.

Radiofrequency ablation versus laser ablation for the treatment of small hepatocellular carcinoma in cirrhosis: a randomized trial.

BACKGROUND AND AIM: In patients with cirrhosis and small hepatocellular carcinoma (HCC), thermal ablation is currently recognized as an effective local treatment. Among thermal procedures, radiofrequency ablation (RFA) is the most diffusely used and is the standard against which any new treatment should be compared. In retrospective studies, laser ablation (LA) resulted as safe and effective as RFA. Therefore, we performed a non-inferiority randomized trial comparing RFA with LA in patients with cirrhosis and HCC within Milan criteria. METHODS: Overall, 140 patients with 157 HCC nodules were randomly assigned to receive RFA or LA. The primary end-point was the proportion of complete tumor ablation (CTA). Secondary end-points were time to local progression (TTLP) and overall survival (OS). RESULTS: Per patient CTA rates after RFA and LA were 97.4% (95% CI, 91.0-99.3) and 95.7% (88.1-98.5), respectively (difference = 1.4%, 95% CI from -6.0% to + 9.0%). Per nodule CTA rates for RFA and LA were 97.4% (91.0-99.3) and 96.3% (89.6-98.7), respectively (difference = 1.1%, from -5.7% to + 8.1%). The mean TTLP was comparable between RFA group (42.0 months; 95% CI, 36.83-47.3) and LA group (46.7 months; 95% CI, 41.5-51.9) (P = .591). The mean OS was 42 months in both groups and survival probability at 1 and 3 years was 94% and 89% in RFA group, and 94% and 80% in LA group. CONCLUSION: LA resulted not inferior to RFA in inducing the CTA of HCC nodules and therefore it should be considered as an evaluable alternative for thermal ablation of small HCC in cirrhotic patients.

Gastric variceal bleeding from segmentary idiopathic splenic vein stenosis with left-sided portal hypertension: An unappreciated complication of pregnancy.

Segmentary idiopathic splenic vein stenosis is a very rare condition. We report a unique case of acute gastric variceal bleeding in a 31-year-old pregnant woman with left-sided portal hypertension from segmentary idiopathic splenic vein stenosis. Hemorrhage was controlled by endoscopic acrylate glue injection and urgent cesarean section allowed successful delivery. The patient declined subsequent intervention and has been on beta-blockers with no bleeding recurrence since then. This condition, its pathophysiological implications and management are discussed.

Preserved liver function, portal thrombosis and absence of oesophageal varices are risk factors for metastasis of hepatocellular carcinoma.

BACKGROUND: Extrahepatic metastases represent a major obstacle for further improving prognosis of hepatocellular carcinoma. AIM: To assess clinical predictors of extrahepatic metastases in a large cohort followed in a single centre. METHODS: We evaluated clinical files of 520 consecutive patients with hepatocellular carcinoma admitted from 1994 to 2002 to our Liver Unit. The following risk factors were assessed: age, gender, hepatitis viruses, alcohol, diabetes, size, number and differentiation of hepatocellular carcinoma, percutaneous biopsy, portal thrombosis, alpha-fetoprotein, Child-Pugh, Cancer Liver Italian Program and Model for End-stage Liver Disease scores, Barcelona Clinic Liver Cancer classification, varices, hepatocellular carcinoma treatment. RESULTS: Extrahepatic metastases were detected in 55/520 patients (10.5%) after 0-72 months (median 15, CI 3-20) from initial evaluation. Lower bilirubin, INR, Child-Pugh and Model for End-stage Liver Disease scores, higher alpha-feto protein levels, portal thrombosis and absence of oesophageal varices were all associated with distant metastases at univariate analysis. Absence of oesophageal varices and portal thrombosis resulted as independent predictors (P = 0.0003 and P = 0.004, respectively) on multivariate logistic regression. Patients with metastases showed poorer survival (3 months) than total hepatocellular carcinoma population (26 months). CONCLUSIONS: Extrahepatic metastases of hepatocellular carcinoma are rare but significantly impair prognosis. Extrahepatic metastases were more frequent in patients with well preserved liver function. Absence of oesophageal varices and presence of portal thrombosis were the strongest risk factors.

Effect of alcohol, cigarette smoking, and diabetes on occurrence of hepatocellular carcinoma in patients with transfusion-acquired hepatitis C virus infection who develop cirrhosis.

AIM: Alcohol drinking, cigarette smoking, and diabetes have been claimed as risk factors for hepatocellular carcinoma in case-control studies. The aim of this study was to define the impact of these risk factors on the development of hepatocellular carcinoma in hepatitis C virus-related liver cirrhosis. METHODS: A historical cohort of 138 patients with posttransfusion hepatitis C virus-related cirrhosis was selected by reviewing all files of patients referred to our liver unit. Sixty-three of them (46%) developed hepatocellular carcinoma. RESULTS: At univariate analysis, risk factors for hepatocellular carcinoma were observed in patients aged above 59 years [P=0.004; relative risk (RR): 2.08, 95% confidence interval (CI): 1.19-3.68], male sex (P<0.001; RR: 2.48, 95% CI: 1.59-3.87), habit of alcohol drinking (P=0.001; RR: 1.89, 95% CI: 1.24-2.88), and duration of alcohol consumption of more than 30 years (P=0.02; RR: 2.08, 95% CI: 0.98-4.40). At Cox regression analysis, only male sex was an independent predictive factor (beta=0.86; P=0.002; hazard ratio=2.4, 95% CI: 1.3-4.1). CONCLUSION: Diabetes, smoking, and alcohol drinking were not independently related to the risk of developing hepatocellular carcinoma in hepatitis C virus-related cirrhosis.

Fatal ischemic acute pancreatitis complicating trans-catheter arterial embolization of small hepatocellular carcinoma: do the risks outweigh the benefits?

Hepatocellular carcinoma (HCC) is an accepted indication for liver transplantation (LT). Pre-LT adjuvant ablation treatments to prevent tumour progression and drop out from the waiting list have been increasingly adopted at most transplant centers. Trans-catheter arterial chemo-embolization (TACE) is frequently used, but the procedure can be difficult and severe complications may arise. Among them, acute ischemic pancreatitis occasionally occurs and may clinically mimic a post-embolization syndrome. Fatal outcomes of this complication have been reported exceptionally but never in patients awaiting LT. The present case raises concern about the widespread application of TACE and highlights the need for a critical evaluation of the risks and benefits to patients with monofocal small HCC who are scheduled for LT. Superselective embolization of the tumour-feeding artery and systematic monitoring of serum pancreatic enzymes after this radiological procedure are recommended.

Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation.

BACKGROUND/AIMS: HCV infection recurs almost in all HCV-positive patients receiving liver transplantation and carries a poor prognosis. Aim of this study was to analyze efficacy and effect on survival of antiviral therapy in this clinical setting. METHODS: Pegylated-interferon alpha-2b and ribavirin were administered at a dose of 1 microg/kg of bwt weekly and 600-800 mg/day. Planned duration of treatment was 24 or 48 weeks according to HCV genotype. Patients who failed to respond at week 24 were considered as non-responders. RESULTS: 61 patients were enrolled. According to intention-to-treat analysis, 44 (72%) patients were considered as treatment failure (31 non-responders, 4 relapsers, 9 dropout). Sustained virological response was achieved in 17 cases (28%). Genotype 2, higher doses of antivirals and absence of histological cirrhosis were predictors of sustained virological response. In the follow up, patients with sustained virological response had a significantly lower mortality compared to patients with treatment failure (chi2=6.9; P<0.01). CONCLUSIONS: Response rate to antiviral therapy in HCV reinfection after liver transplantation is higher if a full dose of antiviral drugs is administered and if treatment starts before histological cirrhosis has developed. Sustained virological response improves patient survival.

Prognostic value of quantitative liver function tests in viral cirrhosis: a prospective study.

BACKGROUND AND AIMS: Widespread application of quantitative liver function tests as a prognostic tool is controversial. In this study we assessed the predictivity of serial evaluations of galactose elimination capacity (GEC) and the monoethylglycinexylidide (MEGX) test on survival in viral cirrhosis, and secondarily we compared these tests with Child-Turcotte-Pugh (CTP) and Model for End Stage Liver Disease (MELD) scores. METHODS: In a cohort of 35 patients with viral cirrhosis, GEC and MEGX were evaluated every 6 months for 24 months and compared with CTP and MELD scores at the same time intervals. The end points were patient death or liver transplantation. RESULTS: Statistically significant differences between dead/transplanted patients and survivors were found for basal values of GEC, MEGX, CTP and MELD. Receiver-operating characteristics curves of CTP and MELD scores showed a higher prognostic accuracy than GEC and MEGX. On multivariate analysis, neither GEC nor MEGX were independent predictors of survival. Repeated-measures analysis of GEC and MEGX did not increase the prognostic accuracy of these tests and did not add useful prognostic information on patient outcome during the following 6 months. CONCLUSIONS: Our data suggest that neither single nor repeated determinations of GEC and MEGX are superior to CTP and MELD scores in predicting prognosis of patients with viral cirrhosis.