Usefulness of the index of NASH - ION for the diagnosis of steatohepatitis in patients with non-alcoholic fatty liver: An external validation study.

BACKGROUND & AIMS: The non-invasive identification of steatohepatitis (NASH) in patients with Non-Alcoholic Fatty Liver Disease is an unmet need in clinical practice. Index of NASH (ION) is a new tool for the prediction of NASH. We aimed to externally validate ION and to compare it with CK-18. Since necroinflammation precedes fibrosis, we also tested ION in combination with non-invasive tools for fibrosis. METHODS: We analysed data from 292 Italian patients (169 Southern cohort, and 123 Northern cohort) with an histological diagnosis of NAFLD. The ION, FIB-4 and NFS scores were calculated according to published algorithms. Serum cytokeratin18-Aspartate396 levels and liver stiffness (LS) by Fibroscan were assessed within three months from liver biopsy. RESULTS: The diagnostic accuracy of ION for the identification of NASH was not as satisfactory as reported (area under the ROC curve, AUROC = 0.687 [95% CI = 0.62-0.75]). The proposed cut-off value ≥50 showed a poor sensitivity (Se) (28%) and a good specificity (Sp) (92%), with a positive predictive value (PPV) of 91% and a negative predictive value (NPV) of 30%. A new cut-off value >26 improved Se (73%) but decreased Sp (60%) (PPV of 84% and a NPV of 43%). ION performed slightly better in obese NAFLD (AUROC = 0.700). The combination of ION and markers of fibrosis did not improve the identification of advanced liver disease. CONCLUSIONS: ION is not feasible for the non-invasive diagnosis of NASH across different populations of NAFLD patients, mainly because its limited reproducibility in non-obese subjects.

Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib.

UNLABELLED: Treatment with sorafenib of patients with advanced hepatocellular carcinoma is challenged by anticipated discontinuation due to tumor progression, liver decompensation, or adverse effects. While postprogression survival is clearly determined by the pattern of tumor progression, understanding the factors that drive prognosis in patients who discontinued sorafenib for any reason may help to improve patient management and second-line trial design. Patients consecutively admitted to three referral centers who were receiving best supportive care following permanent discontinuation of sorafenib for any reason were included. Postsorafenib survival (PSS) was calculated from the last day of treatment to death or last visit available. Two hundred and sixty patients were included in this prospective study, aged 67 years, 60% with hepatitis C, 51% Child-Pugh A, 83% performance status (PS) ≥1, 41% with macroscopic vascular invasion, and 38% with extrahepatic tumor spread. Overall, median PSS was 4.1 (3.3-4.9) months, resulting from 4.6 (3.3-5.7) months for 123 progressors, 7.3 (6.0-10.0) months in 77 with adverse effects, and 1.8 (1.6-2.4) months in 60 decompensated patients (P < 0.001). Postsorafenib survival was independently predicted by PS, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and reason for discontinuation. Two hundred patients potentially eligible for second-line therapy had a PSS of 5.3 (4.6-7.1) months, which was dependent on reasons of discontinuation (P = 0.004), PS (P < 0.001), macrovascular invasion (P < 0.001), and extrahepatic metastases (P < 0.002). CONCLUSION: Discontinuation due to adverse effects in the absence of macrovascular invasion, extrahepatic metastases, and deteriorated PS predicts the best PSS in compensated patients, thereby setting the stage for both improved patient counseling and selection for second-line therapy.

Meta-analysis: the placebo rate of abdominal pain remission in clinical trials of chronic pancreatitis.

OBJECTIVES: Treatment of the pain caused by chronic pancreatitis (CP) is not standardized. Knowledge of the response to placebo in this setting may aid the design of future trials. We aimed at investigating the placebo effect on abdominal pain remission rates in patients with CP. METHODS: MEDLINE, EMBASE, and Scopus were searched, and randomized placebo-controlled trials in CP providing data on abdominal pain remission rates in placebo arms were included. Pooled estimates of the placebo rate were calculated using random-effects logistic regression analysis. Stratum-specific rates for different patients and study-level covariates were calculated to account for heterogeneity. RESULTS: Seven randomized controlled trials (202 placebo-treated patients) met the predefined criteria. The pooled estimate of the placebo rate for pain remission was 19.9% (95% confidence interval, 9%-36%). There was a statistically significant heterogeneity among the studies (I(2) = 76%; P < 0.001). A multicenter design, a run-in period of less than 2 weeks, and absence of a washout in crossover trials were all significant sources of heterogeneity associated with higher placebo responses. CONCLUSIONS: This meta-analysis identifies for the first time the efficacy of placebo for pain in CP and variables determining it. These data provide a sound basis for designing future placebo-controlled randomized clinical trials for the treatment of pain in CP.

Inverse correlation between plasma oxysterol and LDL-cholesterol levels in hepatitis C virus-infected patients.

BACKGROUND: Hepatitis C virus infection is characterised by enhanced oxidative stress, which can be measured quantitatively by plasma oxysterol concentration. These molecules may affect lipid metabolism through the activation of Liver X Receptors. Hepatitis C virus exploits host lipid metabolism to facilitate its replication and diffusion. In our study we aimed to evaluate and highlight the potential pathogenetic role of oxysterols, 7-ketocholesterol and 7-ß-hydroxycholesterol, in hepatitis C virus-related lipid dysmetabolism. METHODS: The study was performed in 42 patients with chronic hepatitis C (93% genotype 1b) and 38 non-alcoholic fatty liver disease patients. Plasma oxysterols 7-ketocholesterol and 7-ß-hydroxycholesterol were determined by isotope dilution gas chromatography/mass spectrometry. RESULTS: Gas chromatography/mass spectrometry revealed higher 7-ketocholesterol (71.2 ± 77.3 vs 30.4 ± 14.5; p<0.005) and 7-ß-hydroxycholesterol (23.7 ± 20.6 vs 11.5 ± 4.9; p<0.001) plasma levels in hepatitis C virus patients. Furthermore, multivariate regression analysis highlighted an inverse independent correlation between high oxysterol levels and low low-density lipoprotein cholesterol (p=0.01 for 7-ß-hydroxycholesterol; p=0.02 for 7-ketocholesterol) in the hepatitis C virus group; in contrast, the non-alcoholic fatty liver disease group showed a direct correlation between oxysterol levels and low-density lipoprotein-cholesterol (p<0.001 for 7-ß-hydroxycholesterol; p=0.002 for 7-ketocholesterol). CONCLUSION: These different correlations reveal profound differences in lipid dysmetabolism between chronic hepatitis C and non-alcoholic fatty liver disease patients.

Two yr mycophenolate mofetil plus low-dose calcineurin inhibitor for renal dysfunction after liver transplant.

We assessed the efficacy and outcome of low through level of calcineurin inhibitors (CNI) and introducing mycophenolate mofetil (MMF) in liver transplant (LT) patients with CNI-related renal dysfunction. Thirty LT patients were converted to combined therapy and compared with 30 patients used as a contemporary control group receiving CNI only. The two groups were matched for sex, age, months after LT, immunosuppressive treatment, creatinine level, presence of diabetes and calculated glomerular filtration rate (GFR) via Cockroft-Gault method. After two years, in the MMF serum creatinine decreased from 1.65 mg/dL (range 1.33-3.5) to 1.4 mg/dL (range 0.9-4.7) (p = 0.002) and GFR increased from 51 mL/min (range 18.9-72.2) to 57.6 mL/min (range 16-92.2) (p < 0.001), whereas the controls not showed any improvement. The logistic regression models employing improvement of creatinine and GFR of at least 10% with respect to baseline as dependent variables showed the use of MMF (p = 0.004 and p = 0.019, respectively) as the only statistically significant parameter. Multiple linear regression analysis identified only MMF as independent predictor of Deltacreatinine and DeltaGFR (p = 0.002 and p < 0.001, respectively). No rejection episode was observed (three in controls). This study demonstrates the medium-term efficacy and safety of MMF plus low dose CNI in reducing nephrotoxicity in LT recipients.

Transcatheter arterial chemoembolization therapy for patients with hepatocellular carcinoma: a case-controlled study.

BACKGROUND & AIMS: Transcatheter arterial chemoembolization (TACE) currently is used as a palliative treatment for patients with unresectable hepatocellular carcinoma (HCC), but its efficacy still is debated. Our aim was to assess the impact of TACE on patient survival and to identify prognostic factors for survival. METHODS: Fifty-six cirrhotic patients with unresectable HCC undergoing at least 1 course of TACE were matched 1:1 for sex, age (in 5-year periods), parameters of Child-Pugh score, Okuda stage, and tumor type with a control group who had received only supportive care. RESULTS: The 2 groups were comparable for cause of cirrhosis, alpha-fetoprotein serum levels, and Cancer of the Liver Italian Program (CLIP) score. The 56 patients in the TACE group received a total of 123 treatment courses. The median follow-up period was 16 months (range, 1-67 mo) in the TACE group and 5 months (range, 1-77 mo) in the supportive care group. Survival rates at 12, 24, and 30 months in patients receiving TACE were 74.3%, 52.1%, and 38.8%, respectively, with a median survival time of 25 months, whereas in supportive care patients the rates were 39.4%, 25.4%, and 19%, respectively, with a median survival time of 7 months (P = .0004). At univariate analysis, TACE, tumor type, presence of ascites, alpha-fetoprotein serum level, CLIP score, and Okuda stage were associated significantly with survival. Only TACE and CLIP score proved to be independent predictors of survival at multivariate analysis. CONCLUSIONS: TACE is an effective therapeutic option for cirrhotic patients with unresectable HCC and a CLIP score of 3 or less.