Eric Nguyen-Khac

Glucocorticoids plus N-Acetylcysteine in Severe Alcoholic Hepatitis

BACKGROUND Mortality among patients with severe acute alcoholic hepatitis is high, even among those treated with glucocorticoids. We investigated whether combination therapy with glucocorticoids plus N-acetylcysteine would improve survival. METHODS We randomly assigned 174 patients to receive prednisolone plus N-acetylcysteine (85 patients) or only prednisolone (89 patients). All patients received 4 weeks of prednisolone. The prednisolone-N-acetylcysteine group received intravenous N-acetylcysteine on day 1 (at a dose of 150, 50, and 100 mg per kilogram of body weight in 250, 500, and 1000 ml of 5% glucose solution over a period of 30 minutes, 4 hours, and 16 hours, respectively) and on days 2 through 5 (100 mg per kilogram per day in 1000 ml of 5% glucose solution). The prednisolone-only group received an infusion in 1000 ml of 5% glucose solution per day on days 1 through 5. The primary outcome was 6-month survival. Secondary outcomes included survival at 1 and 3 months, hepatitis complications, adverse events related to N-acetylcysteine use, and changes in bilirubin levels on days 7 and 14. RESULTS Mortality was not significantly lower in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (27% vs. 38%, P = 0.07). Mortality was significantly lower at 1 month (8% vs. 24%, P = 0.006) but not at 3 months (22% vs. 34%, P = 0.06). Death due to the hepatorenal syndrome was less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (9% vs. 22%, P = 0.02). In a multivariate analysis, factors associated with 6-month survival were a younger age (P<0.001), a shorter prothrombin time (P<0.001), a lower level of bilirubin at baseline (P<0.001), and a decrease in bilirubin on day 14 (P<0.001). Infections were less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group (P = 0.001); other side effects were similar in the two groups. CONCLUSIONS Although combination therapy with prednisolone plus N-acetylcysteine increased 1-month survival among patients with severe acute alcoholic hepatitis, 6-month survival, the primary outcome, was not improved. (Funded by Programme Hospitalier de Recherche Clinique; AAH-NAC ClinicalTrials.gov number, NCT00863785 .).

Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure†‡

Although it is often functional at presentation, acute renal failure has a poor prognosis in patients with cirrhosis. The role of inflammation, a key event in the outcome of cirrhosis, has never been studied in this setting. We aimed to investigate the predictive factors of mortality in patients with cirrhosis and acute functional renal failure, specifically in relation to inflammatory events. One hundred consecutive patients with cirrhosis from 5 French hospitals were prospectively included at the day of onset of acute renal failure. Medical history, treatments, and procedures during the month before inclusion were recorded. Physical examination, blood and urinary chemistries, and renal ultrasound examination were performed. The presence of systemic inflammatory response syndrome (SIRS), infection, and sepsis was assessed. The primary outcome was in‐hospital mortality. The mechanism of renal failure was functional in 83 patients. Causes of renal failure were hypovolemia (34%), hepatorenal syndrome without ongoing infection (17%), hepatorenal syndrome with ongoing infection (16%), nephrotoxicity (2%), and multifactorial (31%). SIRS was observed in 41% of patients, 56% of them with infection. In‐hospital mortality was 68% in patients with SIRS and 33% in patients without (P = 0.001). In multivariate analysis, only model for end‐stage liver disease score and presence of SIRS, but not infection, remained associated with a poor outcome. Conclusion: The presence of SIRS, with or without infection, is a major independent prognostic factor in patients with cirrhosis and acute functional renal failure. This suggests that preventing and treating SIRS could decrease mortality in patients with cirrhosis and acute renal failure. (HEPATOLOGY 2007.)

Is stenting as "a bridge to surgery" an oncologically safe strategy for the management of acute, left-sided, malignant, colonic obstruction? A comparative study with a propensity score analysis.

Objective and Background:Self-expanding metallic stent (SEMS) insertion has been suggested as a promising alternative to emergency surgery for left-sided malignant colonic obstruction (LMCO). However, the literature on the long-term impact of SEMS as “a bridge to surgery” is limited and contradictory. Methods:From January 1998 to June 2011, we retrospectively identified patients operated on for LMCO with curative intent. The primary outcome criterion was overall survival. Short-term secondary endpoints included the technical success rate and overall success rate and long-term secondary endpoints included 5-year overall survival, 5-year cancer-specific mortality, 5-year disease-free survival, the recurrence rate, and mean time to recurrence. Patients treated with SEMS were analyzed on an intention-to-treat basis. Overall survival was analyzed after using a propensity score to correct for selection bias. Results:There were 48 patients in the SEMS group and 39 in the surgery-only group. In the overall population, overall survival (P = 0.001) and 5-year overall survival (P = 0.0003) were significantly lower in the SEMS group than in the surgery-only group, and 5-year cancer-specific mortality was significantly higher in the SEMS group (48% vs 21%, respectively (P = 0.02)). Five-year disease-free survival, the recurrence rate, and the mean time to recurrence were better in the surgery-only group (not significant). For patients with no metastases or perforations at hospital admission, overall survival (P = 0.003) and 5-year overall survival (30% vs 67%, respectively, P = 0.001) were significantly lower in the SEMS group than in the surgery-only group. Conclusions:Our study results suggest worse overall survival of patients with LMCO with SEMS insertion compared with immediate surgery.

Diagnosis of spontaneous bacterial peritonitis in cirrhotic patients by use of two reagent strips.

Objective Spontaneous bacterial peritonitis (SBP) is one of the potentially life-threatening complications in ascitic cirrhotic patients with a mortality rate ranging between 30 and 50%. The improved survival might be explained by a more rapid diagnosis and treatment. The aim of our study was to assess the utility of two reagent strips, the Multistix test and the Combur2 test LN, for the rapid diagnosis of SBP. Methods Thirty-one unselected consecutive cirrhotic patients with ascites were included and a total of 100 paracenteses were performed. All ascitic fluid was analysed with the two reagent strips, leucocyte and polymorphonuclear (PMN) leucocyte cell count and blood-bottle culture if the strips were positive. The strips were considered positive if the colour turned to purple: i.e. grade 3 or 4 for the Multistix test and 2 or 3 for the Combur2 test LN on a colorimetric scale. Results We diagnosed nine infections of which four were SBP defined by PMN ⩾ 250 cells/mm3 and a positive culture in ascitic fluid and five were culture negative neutrocytic ascites (PMN ⩾ 250 cells/mm3 and a negative culture). The results of the two strips were concordant and were negative in only one SBP. The sensitivity, specificity, positive and negative predictive values of these two strips were 89%, 100%, 100% and 99%, respectively. Conclusions These reagent strips are very sensitive and specific for the diagnosis of SBP, allowing immediate commencement of empirical antibiotic therapy. These strips should be used for the diagnosis of SBP, especially on an emergency basis.

Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis

We identified, in the transcriptome analysis of patients with alcoholic hepatitis (AH), osteopontin (OPN) as one of the most up‐regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, western blotting and enzyme‐linked immunosorbent assay. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN−/− mice with alcohol‐induced liver injury. OPN biological actions were studied in human hepatic stellate cells (HSCs) and in precision‐cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH, compared to normal livers and other types of chronic liver diseases, and correlated with short‐term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and matrix metalloproteinase 7) and cleaved OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C single‐nucleotide polymorphism of the OPN gene, compared to patients with alcohol abuse without liver disease. Importantly, OPN−/− mice were protected against alcohol‐induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by lipopolysaccharide and stimulated inflammatory actions in HSCs. Conclusion: Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target. (Hepatology 2013;58:1742–1756)

Noninvasive diagnosis of large esophageal varices by Fibroscan: strong influence of the cirrhosis etiology.

BACKGROUND Large esophageal varices (LOV) were diagnosed by endoscopy in patients with cirrhosis. Noninvasive method would be valuable. AIMS To evaluate the diagnostic performance of Fibroscan for LOV prediction and to investigate the prognostic value of liver stiffness (LS) in cirrhosis. PATIENTS AND METHODS One hundred and eighty-three patients with cirrhosis (103 alcohol, 58 viral, and 22 others) underwent an endoscopy and a Fibroscan. Of those patients, 41 (22.4%) had LOV. RESULTS Median LS was 33.66 kPa (range: 12-75), higher in patients with LOV than those without (51.24 +/- 1.61 vs. 29.81 +/- 1.82 kPa, p < 0.0001), and in alcoholic than nonalcoholic (40.39 +/- 1.75 vs. 25.73 +/- 1.82, p < 0.0001). In whole population, a LS > or =48 kPa predicted LOV with sensitivity, specificity, positive, negative predictive values (PPV, NPV) of 73.2, 73.2, 44.1, and 90.4%, respectively, and an area under ROC curve (AUROC) of 0.75 (CI 95%: 0.69-0.82). For alcoholic cirrhosis, LS was > or =47.2 kPa with sensitivity, specificity, PPV, NPV of 84.6, 63.6, 44, and 92.5%, respectively, AUROC 0.77 (0.68-0.85). For viral cirrhosis, a LS > or =19.8 kPa generated diagnostic values of 88.9, 55.1, 26.7, and 96.4% and 0.73 (0.60-0.84). Sixteen (8.75%) patients died at 1 year. In multivariate analysis, LS was not predictive of mortality. CONCLUSIONS Etiology of cirrhosis has strong impact on LS cutoff for diagnosis of LOV. Studies should be performed with homogenous cirrhosis etiology.

Ribavirin monitoring in chronic hepatitis C therapy: anaemia versus efficacy.

The standard treatment of HCV infection with pegylated interferon-alpha2a or -alpha2b and ribavirin is effective in <50% of HCV genotype-1-infected patients. To improve this figure, it might be desirable to obtain optimal plasma concentrations of the drug by increasing the dose. Unfortunately, there is great interpatient variability in ribavirin pharmacokinetics. In the present review, we describe the mechanism of ribavirin-induced anaemia in detail, evaluate host predictive factors for this harmful side effect and assess the literature data on attempts to improve the sustained virological response rate by increasing the dose of ribavirin. We suggest an optimal steady-state concentration range for ribavirin in monoinfected and coinfected patients. Lastly, we propose that it would be of particular value to monitor ribavirin concentrations in HCV genotype-1-infected patients and (regardless of the genotype) coinfected patients, haemodialyzed patients and obese patients.

Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial

BACKGROUND & AIMS Albumin infusion improves renal function and survival in cirrhotic patients with spontaneous bacterial peritonitis (SBP) but its efficacy in other types of infections remains unknown. We investigated this issue through a multicenter randomized controlled trial. METHODS A total of 193 cirrhotic patients with a Child-Pugh score greater than 8 and sepsis unrelated to SBP were randomly assigned to receive antibiotics plus albumin (1.5 g/kg on day 1 and 1g/kg on day 3; albumin group [ALB]: n=96) or antibiotics alone (control group [CG]: n=97). The primary endpoint was the 3-month renal failure rate (increase in creatinine ⩾50% to reach a final value ⩾133 μmol/L). The secondary endpoint was 3-month survival rate. RESULTS Forty-seven (24.6%) patients died (ALB: n=27 vs. CG: n=20; 3-month survival: 70.2% vs. 78.3%; p=0.16). Albumin infusion delayed the occurrence of renal failure (mean time to onset, ALB: 29.0 ± 21.8 vs. 11.7 ± 9.1 days, p=0.018) but the 3-month renal failure rate was similar (ALB: 14.3% vs. CG: 13.5%; p=0.88). By multivariate analysis, MELD score (p<0.0001), pneumonia (p=0.0041), hyponatremia (p=0.031) and occurrence of renal failure (p<0.0001) were predictors of death. Of note, pulmonary edema developed in 8/96 (8.3%) patients in the albumin group of whom two died, one on the day and the other on day 33 following albumin infusion. CONCLUSIONS In cirrhotic patients with infections other than SBP, albumin infusion delayed onset of renal failure but did not improve renal function or survival at 3 months. Infusion of large amounts of albumin should be cautiously administered in the sickest cirrhotic patients.

Review article: the utility of reagent strips in the diagnosis of infected ascites in cirrhotic patients

Aliment Pharmacol Ther 28, 282–288

BAD, a proapoptotic member of the BCL2 family, is a potential therapeutic target in hepatocellular carcinoma.

Proteins of the BCL2 family are key regulators of apoptosis. Their expression levels are frequently altered in cancers, enabling tumor cells to survive. To gain insight into the pathogenesis of hepatocellular carcinoma (HCC), we performed a comprehensive survey of the expression of the members of the BCL2 family in samples obtained from surgically resected HCCs. Here, we report the occurrence of a new molecular anomaly, consisting of a strong reduction in the expression of the proapoptotic protein BAD in HCC compared with surrounding nontumoral tissue. We investigate the function of BAD in a panel of HCC cell lines. Using gene overexpression and RNA interference, we show that BAD is involved in the cytotoxic effects of sorafenib, a multikinase blocker, which is currently the sole therapeutic drug effective for the treatment of HCC. Finally, we report that ABT-737, a compound that interacts with proteins of the BCL2 family and exhibits a BAD-like reactivity, sensitizes HCC cells toward sorafenib-induced apoptosis. Collectively, our findings indicate that BAD is a key regulator of apoptosis in HCC and an important determinant of HCC cell response to sorafenib. Mol Cancer Res; 8(8); 1116–25. ©2010 AACR.