Triple antiviral therapy in HCV positive patients who failed prior combination therapy

AIM: To assess the efficacy of triple therapy (peginte-rferon or high dose standard interferon, plus ribavirin and amantadine) in nonresponders to prior combination therapy. METHODS: A total of 196 patients were enrolled in a multicenter, open, randomized study. Patients were given 180 mug/wk of peginterferon-alpha-2a (40 kDa) plus ribavirin (800-1000 mg/d) and amantadine (200 mg/d) for 48 wk (group A) or interferon-alpha-2a (6 MU/d for 4 wk, 3 MU/d for 20 wk, and 3 MU tiw for 24 wk) plus ribavirin (800-1000 mg/d) and amantadine (200 mg/d) for 48 wk (group B). RESULTS: Overall sustained virologic response (SVR) was 26.6% (32.1% and 19.5% in group A and B, P = 0.057). Baseline ALT > 120 UI/L (OR 2.4; 95% CI: 1.11 to 5.20; P = 0.026) and HCV RNA negativity after 12 wk (OR 8.7; 95% CI: 3.87 to 19.74; P < 0.0001) were independently associated with SVR. Therapy discontinuation occurred less frequently in patients treated with peginterferon than standard interferon (P = 0.036). CONCLUSION: More than 25% of nonresponders to combination therapy can eradicate HCV infection when retreated with triple therapy, especially if they have a high baseline ALT and are treated with pegylated interferon

Staphylococcus haemolyticus superinfection of Legionella pneumonia during infliximab therapy

We present the case of a 42-year-old man affected by psoriasis with Staphylococcus Haemolyticus superinfection of Legionella pneumonia during infliximab therapy. The introduction of compounds that block TNF-\u3b1 has yielded great benefits for patients affected by selected autoimmune diseases that fail to respond to classic anti-inflammatory agents, but, on the other hand, has led to an increased susceptibility to infections, in particular of those caused by intracellular pathogens, such as L. Pneumophila. Emerging evidence suggests that legionellosis can be complicated by superinfection with other agents, including saprophytic microorganisms, among which coagulasenegative staphylococci. To our knowledge, this is the first report of systemic legionellosis with superinfection by S. haemolyticus, an emerging nosocomial multi-resistant pathogen that commonly causes septicemia, osteomyelitis or endocarditis, but has not so far been associated with necrotizing pneumonia. Despite the optimal antimicrobial therapy for Staphylococcus spp. Pneumonia is still controversial, evidence suggests that in patients with confirmed positivity for methicillin resistant strains, particularly if sensitivity to vancomycin is suboptimal, linezolid should be the first choice therapy, being superior to vancomycin and teicoplanin

The A736V TMPRSS6 Polymorphism Influences Hepatic Iron Overload in Nonalcoholic Fatty Liver Disease

AIMS: Hepatic iron accumulation due to altered trafficking is frequent in patients with nonalcoholic fatty liver disease (NAFLD), and is associated with more severe liver damage and hepatocellular carcinoma. The p.Ala736Val TMPRSS6 variant influences iron metabolism regulating the transcription of the hepatic hormone hepcidin, but its role in the pathogenesis of iron overload disorders is controversial. Aim of this study was to evaluate the whether the TMPRSS6 p.Ala736Val variant influences hepatic iron accumulation in a well-characterized series of Italian patients with histological NAFLD. METHODS: 216 patients with histological NAFLD. TMPRSS6 and HFE variants were assessed by allele specific PCR, liver histology by the NAFLD activity score and Perls' staining for iron. RESULTS: Homozygosity for the p.736Val allele previously linked to higher hepcidin did not influence transferrin saturation (TS), but was associated with lower hepatic iron stores (p\u200a=\u200a0.01), and ferritin levels (median 223 IQR 102-449 vs. 308 IQR 141-618 ng/ml; p\u200a=\u200a0.01). Homozygosity for TMPRSS6 p.736Val was nearly associated with lower ballooning (p\u200a=\u200a0.05), reflecting hepatocellular damage related to oxidative stress. The influence of TMPRSS6 on hepatic iron accumulation was more marked in patients negative for HFE genotypes predisposing to iron overload (p.Cys282Tyr + and p.His63Asp +/+; p\u200a=\u200a0.01), and the p.736Val variant was negatively associated with hepatic iron accumulation independently of age, gender, HFE genotype, and beta-thalassemia trait (OR 0.59, 0.39-0.88). CONCLUSIONS: The p.Ala736Val TMPRSS6 variant influences secondary hepatic iron accumulation in patients with NAFLD

Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis

AIM: To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH). METHODS: We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d in males or females) or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology (n = 100) or ultrasound (n = 23). The PNPLA3 rs738409 single nucleotide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay (assay on demand, Applied Biosystems). The association of the PNPLA3 I148M protein variant (p.I148M) with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis. RESULTS: PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine aminotransaminase (ALT) levels. The p.148M variant was also associated with higher aspartate aminotransferase (P = 0.0014) and ALT levels (P = 0.017) at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity (stage) of fibrosis (estimated coefficient 0.56 \ub1 0.27, P = 0.041). In the overall series of patients, the p.148M variant was associated with cirrhosis in lean (P = 0.049), but not in overweight patients (P = not significant). At logistic regression analysis, cirrhosis was associated with BMI 65 25 (OR 1.82, 95% CI: 1.02-3.55), ferritin > 1000 ng/mL at diagnosis (OR 19.3, 95% CI: 5.3-125), and with the G allele in patients with BMI < 25 (OR 3.26, 95% CI: 1.3-10.3). CONCLUSION: The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH

The immunopathogenesis of alcoholic and nonalcoholic steatohepatitis : two triggers for one disease?

Alcoholic liver disease and nonalcoholic liver disease represent a leading cause of liver disease and share similar pathogenic mechanisms among which activation of the immune system plays a key role. The main events consist in (a) activation of Kupffer cells via TLR-4 by LPS and fatty acids (b) complement activation (c) increased release of proinflammatory mediators (d) alteration in NK and NKT cell number/activity (e) activation of the adaptive immune system. At the same time, activation of intracellular pro-inflammatory pathways by cytokines and bacterial products, inhibit insulin signaling favoring lipogenesis, metabolic alterations, and cell damag

Beyond hereditary hemochromatosis : new insights into the relationship between iron overload and chronic liver diseases

Following the model of hereditary hemochromatosis, the possible role of iron overload as a cofactor for disease progression in acquired liver diseases has been investigated with controversial results. In recent years, progress has been made in understanding the regulation of iron metabolism, thereby allowing the evaluation of the mechanisms linking liver diseases to excessive iron accumulation. Indeed, deregulation of the transcription of hepcidin, emerging as the master regulator of systemic iron metabolism, has been implicated in the pathogenesis of hepatic iron overload in chronic liver diseases. Whatever the cause, hepatocellular iron deposition promotes liver fibrogenesis, while an emerging possible aggravating factor is represented by the strong link between iron stores and insulin resistance, a recently recognized risk factor for the progression of liver diseases. Overall, these pathogenic mechanisms, together with the known proliferative and mutagenic effect of excess iron, converge in determining an increased susceptibility to hepatocellular carcinoma. Finally, an association between serum ferritin levels and mortality in patients with end-stage liver disease has recently been reported.Prospective, randomized studies are required to evaluate whether iron depletion may reduce fibrosis progression, hepatocellular carcinoma development, and eventually mortality in patients with chronic liver diseases