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Troponin I (TnI) false positive results have been reported in patients affected by immune disorders. We report the case of a 74-year-old woman affected by cryoglobulinemic vasculitis, admitted to the Emergency Room because of a lipotimic episode. A marked elevation of TnI plasma concentration was confirmed in multiple determinations, despite the absence of symptoms or electrocardiogram findings suggesting myocardial infarction. TnI plasma concentration was reported normal after re-testing with a different commercial kit. A false TnI positivity should be considered in patients with immune disorders, especially if seropositive for rheumatoid factor, when the clinical context does not suggest myocardial infarction.

The association between cancer and immune-mediated rheumatic conditions is controversial, especially as far as polymyalgia rheumatica (PMR) is concerned. Furthermore, no clinical feature has been shown to be suggestive of a paraneoplastic rheumatic syndrome. With the present study, we aim to address both these issues. The study population comprised N = 1750 patients, including N = 100 with PMR, who attended our tertiary immuno-rheumatology clinic between January 1, 2005 and November 30, 2012. A rheumatic disease was deemed paraneoplastic if cancer had been diagnosed in the 2 years preceding or following its onset. The probability of a significant association between a specific rheumatic disease and cancer was evaluated by computing the odds ratio (OR): N = 702 patients with osteoarthritis serving as controls. Furthermore, clinical features distinguishing paraneoplastic rheumatic diseases were searched for by univariate and multivariate analysis. Sjogren’s syndrome (SS) [OR 3.6 (CI 95% 1.7–7.5)], PMR (OR 5.1 CI 95% 2.9–8.9), dermatomyositis/polymyositis [OR 12.09 (CI 95% 2.6–55.8)] and vasculitis [OR 3.70 (CI 95% 1.81–7.52)] are associated with cancer. At multivariate analysis, older age is associated with cancer among SS patients (p = 0.03), while in the PMR group, older age, male gender, and ≥6 tender joints are independent predictors of paraneoplastic PMR (p

BACKGROUND & AIMS: Overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC) due to the mutual influence of cirrhosis and active malignancy in dictating patient's mortality. The ALBI grade is a recently described index of liver dysfunction in hepatocellular carcinoma, based solely on albumin and bilirubin levels. Whilst accurate, this score lacks cross-validation, especially in intermediate stage HCC, where OS is highly heterogeneous. METHODS: We evaluated the prognostic accuracy of the ALBI grade in estimating OS in a large, multi-centre study of 2426 patients, including a large proportion of intermediate stage patients treated with chemoembolization (n=1461) accrued from Europe, the United States and Asia. RESULTS: Analysis of survival by primary treatment modality confirmed the ALBI grade as a significant predictor of patient OS after surgical resection (p

Hepatitis C Virus (HCV) is a major public health problem worldwide. While highly efficacious directly-acting antiviral agents have been developed in recent years, their high costs and relative inaccessibility make their use limited. Here, we describe new 1-(ω-phenoxyalkyl)uracils bearing acetanilide fragment in 3 position of pyrimidine ring as potential antiviral drugs against HCV. Using a combination of various biochemical assays and in vitro virus infection and replication models, we show that our compounds are able to significantly reduce viral genomic replication, independently of virus genotype, with their IC50 values in the nanomolar range. We also demonstrate that our compounds can block de novo RNA synthesis and that effect is dependent on a chemical structure of the compounds. A detailed structure-activity relationship revealed that the most active compounds were the N(3)-substituted uracil derivatives containing 6-(4-bromophenoxy)hexyl or 8-(4-bromophenoxy)octyl fragment at N(1) position.

Previous cross-sectional studies have shown that hepatitis C virus (HCV) infection had been the main agent associated with liver cirrhosis in Italy. Abstract BACKGROUND: Previous cross-sectional studies have shown that hepatitis C virus (HCV) infection had been the main agent associated with liver cirrhosis in Italy. AIM: To assess epidemiological, laboratory and clinical features of liver cirrhosis in Italy in 2014. PATIENTS: Out of the 2557 consecutive subjects evaluated in 16 hospitals located throughout Italy in 2014, 832 (32.6%) had liver cirrhosis and were enrolled in this study. RESULTS: The mean age of subjects was 60.3years, with a male/female ratio of 1.7; 74.9% of cases had Child A cirrhosis and 17.9% superimposed hepatocellular carcinoma. HCV infection, alone or in combination with other aetiologic agents, was responsible of 58.6% of cases, HBV aetiology accounted for the 17.6% and alcohol abuse for the 16.0%. Compared with virus-related cirrhotic patients, those alcohol-related more frequently showed decompensation (p=0.02). CONCLUSIONS: Compared to previous surveys performed in 1992 and in 2001, we observe a statistically significant (p

Type 2 Diabetes Mellitus (T2DM) and pre diabetes prevalence is increasing worldwide at an alarming rate. Though many risk factors have been identified, the most appropriate strategy to identify when and who should undergo a more accurate screening, which could allow an earlier diagnosis and a more efficient prevention of complications, is still a matter of debate. In this review we present data from a cohort of 2126 asymptomatic non diabetic subjects, who underwent an Oral Glucose Tolerance Test (OGTT). We have discussed our results sub-classifying our population according to the risk factors for diabetes development previously proposed by the American Diabetes Association. According to our data, OGTT is able to identify a substantial proportion of subjects with prediabetic conditions who, if untreated, could progress to overt T2DM and potentially encounter serious health problems, even in non-at risk subgroups, such as subjects with a normal fasting glucose, who have a normal lipid profile and arterial pressure, who do not have a familiar history of diabetes and who do not fulfil classification criteria for metabolic syndrome. Interestingly, a further proportion of subjects fulfil OGTT criteria for diagnosis of T2DM in each of these subgroups. Therefore, we believe that OGTT execution should be advocated as a screening test in asymptomatic populations to search prediabetes before diabetes.

Growth arrest specific 6 (Gas6) has neurotrophic and neuroinflammatory functions, and may play a role in Alzheimer's disease (AD). In keeping with this hypothesis, we observed that cerebrospinal fluid (CSF) Gas6 is increased in AD patients compared to controls (63 versus 67 subjects; median value 13.3 versus 9.1 ng/ml; p

Non-invasive ventilation (NIV) delivered in an intensive care unit (ICU) has become the cornerstone in the treatment of patients with severe chronic obstructive pulmonary disease (COPD) exacerbations. A trend towards managing these patients in non-ICU setting has emerged in recent years, although out-of-hospital survival by this approach and how to prognosticate it is unknown. We aimed to investigate these issues. We consecutively recruited 100 patients (49 males; median age 82 years) who received NIV treatment for acute respiratory failure due to COPD exacerbation in non-ICU medical wards of our hospital, between November 2008 and July 2012. We assessed survival (both in-hospital and out-of-hospital) of all these patients, and analyzed baseline parameters in a Cox proportional hazards model to develop a prognostic score. The median survival in the study population was 383 days (240–980). Overall survival rates were 71.0, 65.3, and 52.7 % at 1, 3, and 12 months, respectively. Age >85 years, a history of heart disorders and a neutrophil count ≥10 × 109 were associated with higher mortality at Cox’s analysis (χ 2 = 35.766, p = 0.0001), and were used to build a prognostic score (NC85). The presence of two or more factors determined the deepest drop in survival (when NC85 ≥2, mortality at 1, 3, and 12 was 60.7, 70.4, and 77.2 %, respectively, while when NC85 = 0 were 4.0, 4.0, and 14.0 %). A simple model, based on three variables (age, neutrophil count and history of heart disease), accurately predicts survival of COPD patients receiving NIV in a non-ICU setting.

Human toxocariasis has been reported to cause a broad spectrum of neurological syndromes, including encephalitis, meningitis and meningo-radiculitis. Nevertheless, cerebral infection by Toxocara may go undiagnosed due to its rarity, elusive symptoms and lack of availability of appropriate testing. We report the case of a 54-year-old man who presented with abdominal pain and paralytic ileus approximately 3 weeks after having eaten raw snails (a folk remedy for peptic ulcer). Three weeks later, marked eosinophilia ensued, associated with mental clouding, nystagmus, diplopia, peripheral limbs ataxia, urinary retention, slackened deep tendon reflexes, arthralgias and myalgias. Cerebrospinal fluid (CSF) examination demonstrated an eosinophilic meningitis, and Toxocara canis cerebral infection was diagnosed by positive serology and by the detection of T. canis DNA in the CSF. The patient made a full recovery following treatment with albendazole and corticosteroids. Physicians should be aware of this rare presentation of toxocariasis, whose diagnosis is, today, facilitated by molecular biology techniques. A history of ingestion of raw snails may alert the clinician to consider the possibility of such an uncommon condition.

Peroxisome proliferator-activated receptor-gamma (PPARγ) is expressed by different cell types in the joints and plays a relevant anti-inflammatory role in various diseases. This pilot study aimed to evaluate PPARγ expression in monocytes/macrophages isolated from RA patients as compared with healthy subjects, the relationships between PPARγ expression, MMP-9 activity and disease, and the influence of therapy with anti-rheumatic drugs on these parameters.Thirty RA patients of both sexes (treated with CSs and MTX, mainly) and 15 healthy volunteers were enrolled in this study. Disease severity was evaluated by the 28-joint disease activity score (DAS-28). Monocytes and monocyte-derived macrophages (MDMs) were isolated by standard procedures. PPARγ protein and mRNA expression were assessed by immunoblotting and real-time PCR, respectively; MMP-9 activity was determined by gelatin zymography. Moreover, we checked the ability of 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ, a PPARγ agonist), MTX and methylprednisolone (MP) to affect PPARγ expression and lipopolysaccharide (LPS)-induced MMP-9 activity.Monocytes/MDMs from RA patients have significantly enhanced PPARγ expression (both protein and mRNA) and MMP-9 activity as compared with healthy donors. Interestingly, cells from patients with less active disease (DAS-283.2) present higher PPARγ protein expression and lower MMP-9 activity than RA patients with DAS-283.2. At therapeutic concentrations, MTX and MP increase in vitro PPARγ protein expression and inhibit LPS-induced MMP-9 activity.PPARγ expression in human monocytes/MDMs could represent an indicator of disease activity and therapy efficacy in RA because patients with a DAS-28 score3.2 show the highest expression.

Viral hepatitis has been treated empirically for more than 30 years with interferon (IFN)-based therapies, although in the early days of the IFN era, very little was known regarding the mechanisms of action through which IFN acts and the strategies that viruses deploy to escape the antiviral state induced by the activation of the IFN system. Over the years, we have learned how key effector molecules in this system are expressed and interact. On the verge of novel, IFN-free regimens for viral hepatitis, we can take advantage of this huge bulk of research data in order to gain better understanding of how resistance to IFN develops in our patients, to use IFN more effectively in conjunction with other drugs and to devise new treatments.

The interleukin 28B (IL-28B) rs12979860 C/T polymorphism is a predictor of spontaneous and treatment-induced hepatitis C virus (HCV) clearance. The C/C genotype is associated with higher serum cholesterol, predictor of a favorable outcome in chronic hepatitis C. Whether IL-28B polymorphism and serum cholesterol play a role in modulating the history of mild hepatitis C is unknown. To clarify this issue, 93 untreated patients infected with HCV with normal or near-normal transaminases and an initial Ishak staging score ≤1 were investigated retrospectively in the longitudinal study (median histological follow-up of 10 years). An additional confirmatory cohort of 143 patients with chronic HCV infection and abnormal levels of transaminases was evaluated in the cross-sectional study. In the longitudinal study, at the end of follow-up, Ishak staging scores progressed more frequently among carriers of a T/* allele who had a baseline serum cholesterol ≤175 mg/dl than in remaining patients: 6/36 (change ≤0), 15/45 (change 1–2), 6/12 (change ≥3), improvement chi-square P

Vitamin D receptor (VDR) polymorphisms may confer susceptibility to immunologically mediated liver diseases. We aimed to verify whether recipient VDR polymorphisms might affect the incidence of acute cellular rejection (ACR) of the graft after liver transplantation (LT). Two hundred and fifty-one liver-transplanted patients surviving at least 1month were studied. ACR in the first post-LT year was graded according to the Banff score. Recipients genotyping for VDR polymorphic sites (FokI C>T, BsmI G>A, ApaI T>G, TaqI T>C) was performed. A significant difference was found between patients with and without ACR episodes in allele frequencies of BsmI (G: 0.660 vs. 0.545, P=0.017) and TaqI (T: 0.667 vs. 0.543, P=0.010). Patients carrying the G-*-T/G-*-T diplotypes of the BsmI G>A, ApaI T>G and TaqI T>C experienced more frequently ACR: 33/79 Vs 42/172, P=0.005. Carriage of G-*-T/G-*-T diplotypes was an independent predictor of ACR (OR 2.41, P=0.006), with CMV reactivation (OR 2.34, P=0.033) and HCV aetiology (OR 1.86, P=0.036). In conclusion, recipient VDR polymorphic loci are strongly associated with ACR occurrence during the first year after LT. The knowledge of VDR genetic polymorphisms may be helpful in identifying recipients at higher risk of ACR and in selecting them for a more aggressive immunosuppressive therapy.

Circulating human monocytes, a functionally and phenotypically heterogeneous population, are emerging as fundamental cell types in rheumatoid arthritis (RA). The aim of this pilot study was to assess the correlation, if any, among anti-rheumatic drug therapy, circulating CD14(+)CD16(+) monocytes and validated clinical scales (e.g., DAS28 score and ultrasonography US7 score) of disease severity in RA. Thirty consecutive RA patients, either naive or under disease-modifying anti-rheumatic drugs (DMARDs) or biological therapy, and 10 age-matched healthy volunteers, were enrolled. Monocytes were prepared from heparinized blood samples; surface expression of CD14 and CD16 was determined by flow cytometry. RA patients presented a significantly higher percentage of CD14(+)CD16(+) monocytes, as compared to healthy subjects. There was a good correlation between DAS28 clinical score and the ultrasound composite score US7 (r=0.66), as well as between both scores and the percentage of CD14(+)CD16(+) monocytes (r=0.43 and 0.47, respectively). Naive RA patients had the highest expression (19.2±3.2%) of CD14(+)CD16(+) monocytes and elevated DAS28 score; patients on DMARDs presented a 7-fold increased expression of CD14(+)CD16(+) monocytes, relatively to healthy volunteers (2.1±1.4%), and an intermediate disease severity. The RA patients treated with biological therapy had a low percentage of CD14(+)CD16(+) monocytes (5.1±3.6%; p

Background: Level I evidence supports the use of sorafenib in patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma, where heterogen

Aliment Pharmacol Ther 2012; 35: 92–104 Summary Background Preliminary data suggest that performance of non-invasive markers for liver fibrosis in hepatitis C may improve when combined. Three algorithms based on the combination of Fibrotest, Forns’ index and AST-to-platelet ratio (APRI) have been proposed: Sequential Algorithm for Fibrosis Evaluation (SAFE biopsy); Fibropaca algorithm; Leroy algorithm. Aim To compare three algorithms to diagnose significant fibrosis (≥F2 by METAVIR) and cirrhosis (F4). Methods A total of 1013 HCV monoinfected cases undergoing liver biopsy were consecutively enrolled in seven centres. Fibrotest, APRI and Forns’ index were measured at the time of liver biopsy, considered the reference standard. Results Overall, performance of combination algorithms was significantly higher than the single non-invasive methods (P

Objectives. To verify if autoimmune/inflammatory rheumatic disease (ARD) patients were more refractory to PTH suppression by 25(OH) vitamin D (VITD). Methods. Data from 105 consecutive ARD patients (including RA, PMR, spondyloarthritis and other CTDs) attending a tertiary-level immuno-rheumatology clinic and 1542 subjects tested at our central laboratory from 2008 to 2010 (controls) were collected. After exclusion of patients with renal failure, primary hyperparathyroidism and hypercalcaemia (n=522), plasma VITD, PTH, calcium and phosphate concentrations were compared between these two groups. Results. Plasma VITD concentrations were

Aliment Pharmacol Ther 2011; 34: 1202–1216 Summary Background Performance of non-invasive fibrosis biomarkers may be influenced by aetiology of chronic liver disease (CLD) and the stages of hepatic fibrosis, but large-scale studies are pending. Aim To investigate the effect of aetiogy and stages of hepatic fibrosis on the performance of fibrosis biomarkers. Methods A total of 2411 patients with compensated CLD (HCV = 75.1%, HBV = 10.5%, NASH = 7.9%, HIV/HCV = 6.5%) were consecutively enrolled in 9 centres. APRI, Forns’index, Lok index, AST-to-ALT ratio, Fib-4, platelets and Fibrotest-Fibrosure were tested against liver biopsy, considered the gold standard. The effect of the stages of hepatic fibrosis to diagnose significant fibrosis and cirrhosis (≥F2 and F4 respectively) was investigated through difference between advanced and non-advanced fibrosis stages (DANA). Performance was expressed as observed area under the ROC curve (ObAUROC) and AUROC adjusted for DANA (AdjAUROC). Results Performance of APRI and Fibrotest-Fibrosure was higher than other biomarkers. In all aetiologies, AdjAUROC was higher than ObAUROC. APRI showed its best performance in HCV monoinfected cases, with an AdjAUROC of 0.77 and 0.83 for ≥F2 and F4 respectively. In HBV and non-alcoholic steatohepatitis (NASH) patients, its performance was poor (AdjAUROC 0.73), except for ≥F2 in NASH (AdjAUROC = 0.64). Performance of all biomarkers was reduced in HCV cases with normal ALT. Conclusions Aetiology is a major factor influencing the performance of liver fibrosis biomarkers. Even after correction for DANA, APRI and Fibrotest-Fibrosure exhibit the best performance. However, liver biopsy is not replaceable, especially to diagnose ≥F2 and in HCV carriers with normal ALT.

This study aimed to determine whether the single-nucleotide polymorphism (rs12979860 C/T) of the interleukin 28B (IL-28B) gene, which is associated with hepatitis C virus (HCV) clearance, is also associated with fibrosis in chronic HCV infection.An RFLP-PCR technique was used to genotype 629 HCV-positive patients (200 with cirrhosis) and 428 healthy control subjects.The genotype frequencies in the controls and chronic hepatitis C patients were as follows: C/C 47.0% vs. 32.6%, C/T 41.8% vs. 52.8% and T/T 11.2% vs. 14.6% (p0.0001). The C allele frequency was higher in HCV-2- (0.635) and 3- (0.692) infected patients in comparison to those infected with HCV-1 (0.550) or 4-5 (0.600) (p0.001). Infected T/T homozygotes had a mean staging score higher than other patients (3.50 vs. 3.04, p0.05).IL-28B rs12979860 C/T polymorphism is associated with a greater likelihood of HCV persistence, particularly in HCV genotypes 1 and 4. The T allele affects the severity of liver fibrosis.

Background and aim: The PNPLA3 rs738409 C>G polymorphism has been found to be strongly associated with non-alcoholic fatty liver disease and with alcoholic liver disease. Whether the PNPLA3 rs738409 polymorphism could be a risk factor for the development of hepatocellular carcinoma (HCC) in cirrhosis patients is unknown. Methods: This study included 483 (344 males) consecutive Italian patients of Caucasian ethnicity affected by cirrhosis, of whom 279 had undergone transplantation for end-stage liver disease while 204 had been referred to our liver and transplant unit for the diagnosis of cirrhosis. The aetiologies were hepatitis C virus=209, hepatitis B virus=76, alcohol=166, metabolic=32. Ile148Met rs738409 transversion was genotyped using an restriction fragment length polymorphism-based assay. Results: The genotype frequencies of the rs738409 polymorphism were distributed differently in patients with cirrhosis C/C=168, C/G=220, G/G=95 vs controls C/C=218, C/G=175, G/G=35 (PG polymorphism is associated with cirrhosis. In synergy with gender, this polymorphism is a strong predictor of HCC occurrence among patients with cirrhosis.

Background & Aims A single nucleotide polymorphism (rs12979860 C/T) 3kb upstream of the interleukin 28B ( IL-28B ) gene was shown to be associated with hepatitis C clearance. We verified whether this association also translates into a different genotype distribution at the end of the disease trajectory. Methods A RFLP-PCR technique was used to genotype 412 patients with cirrhosis due to hepatitis C ( n =199), hepatitis B ( n =75), alcohol ( n =110), and other causes ( n =28), of whom 256 underwent liver transplantation (OLT). Hepatocellular carcinoma (HCC) was demonstrated in the native liver of 85 OLT patients, 52 with viral cirrhosis, and 33 with non-viral cirrhosis respectively. A group of 292 patients (235 HCV and 57 HBV positive) with mild chronic hepatitis and 344 healthy subjects served as controls. Results A significant difference ( p =0.0005) was observed in IL-28B rs12979860 genotype frequencies between patients with viral cirrhosis (C/C=99, C/T=137, T/T=38) and those with non-viral cirrhosis (C/C=72, C/T=58, T/T=8). Patients with HCV related cirrhosis carried more frequently the T/T genotype in comparison to mild hepatitis C or HBV-related cirrhosis. IL-28B rs12979860 genotype frequencies were C/C=23, C/T=50, T/T=12 among OLT patients with cirrhosis complicated by HCC, and C/C=79, C/T=78, T/T=14 among patients with cirrhosis not complicated by HCC ( p Conclusions IL-28B rs12979860 C/T polymorphism T allele is more prevalent in patients with viral cirrhosis due to HCV in comparison to other aetiologies and to patients with mild chronic hepatitis C. Among OLT patients, carriage of this allele seems to augment the risk of developing HCC.

The widely accepted interleukin-28B (IL-28B) rs12979860 C/T polymorphism and the more recently proposed vitamin D serum concentration are two novel predictors of the response to antiviral treatment in chronic hepatitis C virus (HCV) infection. This study aimed to verify whether the IL-28B rs12979860 C/T polymorphism and pretreatment serum vitamin D levels have independent or complementary roles in predicting the rates of sustained viral response (SVR). The present study included 211 consecutive, treatment-naive chronic HCV patients who had their pretreatment serum 25-OH vitamin D level and IL-28B rs12979860 C/T genotype determined. Overall, SVR was achieved by 134/211 (63.5%) patients and by 47/110 (42.7%) patients infected with difficult-to-treat HCV genotypes. On multivariate analysis, SVR was predicted by the HCV genotype, the IL-28B rs12979860 C/T polymorphism, and gamma-glutamyl transpeptidase, HCV RNA, cholesterol, and 25-OH vitamin D serum levels, with an area under the receiver operating characteristic (ROC) curve of 0.827. When difficult-to-treat HCV genotypes were analyzed separately, the SVR was predicted by the IL-28B rs12979860 C/T polymorphism, viral load, and serum vitamin D level, with an area under the ROC curve of 0.836. Moreover, by categorizing these latter patients into four groups—C/C homozygotes with vitamin D levels >20 ng/mL (group A) or ≤20 ng/mL (group B) and C/T heterozygotes or T/T homozygotes with vitamin D levels >20 ng/mL (group C) or ≤20 ng/mL (group D)—a significant linear trend was observed, with SVR rates in the following descending order: group A, 18/21 (85.7%); group B, 6/11 (54.5%); group C, 14/38 (36.8%); and group D, 9/40 (22.5%) (P < 0.0001). Conclusion: Vitamin D serum levels are complementary to the IL-28B rs12979860 C/T polymorphism in enhancing the correct prediction of the SVR in treatment-naive chronic hepatitis C. (HEPATOLOGY 2011;)

Background and Aim: Carriage of the apolipoprotein E (Apo E) variants, E2, E3 and E4, affects cholesterol metabolism and may be involved in the persistence of hepatitis C virus (HCV) infection. Our aim was to verify whether carriage of specific Apo E variants modulates the course of hepatitis C. Methods: We studied a cohort of 116 HCV-positive patients (49 male subjects) with persistently normal transaminases and an Ishak staging score ≤ 2 at an initial biopsy. These untreated patients underwent regular clinical monitoring (median histological follow up: 10 years). Apo E variants were genotyped and results were related to the histological outcome. Results: The mean ± standard deviation staging scores were 0.9 ± 0.7 at entry versus 1.9 ± 1.2 at the end of follow up, P 190 mg/dL were more likely to have a favorable outcome (final vs initial staging score increased in 7/66, did not change in 10/46, and decreased in 3/4, P

In immune-competent patients, higher vitamin D levels predicted sustained viral response (SVR) following interferon (INF) and ribavirin therapy for chronic hepatitis C. This study aimed to verify the influence of vitamin D serum levels and/or vitamin D supplementation in predicting SVR rates for recurrent hepatitis C (RHC). Forty-two consecutive patients were treated for RHC with combination therapy with INF-α and ribavirin for 48 weeks. Vitamin D serum levels were measured in all patients before antiviral therapy. In 15 patients oral vitamin D3 supplementation was administered to avoid further bone loss. SVR was observed in 13 patients; it was achieved in 1/10 severely vitamin D deficient (≤ 10 ng/ml) patients, in 6/20 deficient (>10 and ≤ 20 ng/ml) and in 6/12 with near normal (> 20 ng/ml) 25-OH vitamin D serum levels (P < 0.05). Cholecalciferol supplementation, in the presence of a normal or near normal baseline vitamin D concentration, (improvement of chi-square P < 0.05, odds ratio 2.22) and possessing a genotype other than 1 (improvement of chi-square P < 0.05, odds ratio 3.383) were the only variables independently associated to SVR. In conclusion, vitamin D deficiency predicts an unfavourable response to antiviral treatment of RHC. Vitamin D supplementation improves the probability of achieving a SVR following antiviral treatment.

Interleukin-1 beta (IL-1 beta) genetic polymorphisms and IL-1 receptor antagonist (IL1RN) variable number tandem repeat (VNTR) seem to be related with the occurrence of chronic diseases. This study aimed to verify whether IL-1 beta -511C/T, -31T/C, +3953C/T and IL1RN VNTR were associated to the development of liver cirrhosis. Two hundred forty cirrhotic patients were involved in the study. A significant trend was detected, for increasing cirrhosis frequencies, grouping the patients as follows: females and males carrying neither the IL-1 beta (-511 -31) T-C/T-C or T-C/(T-T or C-C) diplotypes nor any IL1RN A2 allele (138/292), males carrying either the IL-1 beta T-C/T-C or T-C/(T-T or C-C) diplotypes or at least one IL1RN A2 allele (74/147) and males carrying either the IL-1 beta T-C/T-C or T-C/(T-T or C-C) diplotypes and at least one IL1RN A2 allele (28/37) (p0.01). IL-1 beta polymorphisms are associated with the occurrence of end stage liver disease. IL-1 beta inflammatory activity appears more pronounced in males.

Owing to a highly variable natural course, the benefits of a successful treatment may be marginal for many hepatitis C patients. Therefore, the ability to discriminate patients with chronic hepatitis C virus (HCV) infection at risk of severe consequences, to whom more aggressive treatment strategies should be directed, would be important for clinicians.To review the status of medical research in this area and its transferability to today's medical diagnostics.A Medline search was conducted with the keywords hepatitis C, fibrosis, cirrhosis, polymorphism(s) and outcome. Other papers were identified from personal knowledge by the authors or reviewing the references of articles otherwise selected.The vast majority of data were generated by a candidate-gene strategy, ending in conflicting or irreproducible results. Lack of consistent associations between specific single nucleotide polymorphisms and fibrosis severity in hepatitis C has many reasons, including small sample size, mixed ethnicity of the populations studied, and heterogeneity of outcome measures. Recently, assaying tens of thousands of single nucleotide polymorphisms in a multistage research strategy and using a combination of several different single nucleotide polymorphisms have set the stage for future, high-quality studies. This will hopefully close the gap between research and clinical applications in this area.

Background Occult hepatitis B virus (HBV) infection can be defined as the long-lasting persistence of viral genomes in the liver tissue, and sometimes also in the serum at low levels of viremia in individuals with undetectable HBV surface antigen (HBsAg). Viral replication can be reactivated by immunosuppressive therapies or immunologic diseases, leading to the development of typical hepatitis B. Methods All patients on the waiting list for renal transplantation at the only 2 transplant centers in our region (Piemonte, Italy) were checked for the presence of occult HBV infection by an highly sensitive quantitative HBV-DNA polymerase chain reaction (PCR) assay (nested PCR); the only exclusion criterion was HBsAg-positivity. The enrollment lasted from October 1, 2006, to May 31, 2007. The prospective follow-up will continue for 5 years. Results HBV-DNA sequences were detected in blood samples from 10 of 300 cases examined (3.3%), being more frequent among Asian (1/3; 33.3%) and African (1/16; 6.25%) subjects as compared with the Caucasians (8/281; 2.8%; P = .011), among anti-hepatitis C virus (HCV) positive versus HCV negative patients (3/32 [9.3%] vs 7/268 [2.6%]; P = .004) and mainly among patients with a previous history of overt liver diseases (3/22 [14%] vs 7/278 [2.5%]; P = .019). HBV-DNA sequences became undetectable at 1 month after renal transplantation in 3 patients; the follow-up is in progress for these and the other patients. Conclusion Occult HBV infection occurs in patients undergoing renal transplantation. Longer observation and prospective studies will clarify the clinical impact of this occult infection on transplant outcomes and the possibility of viral reactivation related to immunosuppressive therapy.

The staging of liver fibrosis is pivotal for defining the prognosis and indications for therapy in hepatitis C. Although liver biopsy remains the gold standard, several noninvasive methods are under evaluation for clinical use. The aim of this study was to validate the recently described sequential algorithm for fibrosis evaluation (SAFE) biopsy, which detects significant fibrosis (≥F2 by METAVIR) and cirrhosis (F4) by combining the AST-to-platelet ratio index and Fibrotest-Fibrosure, thereby limiting liver biopsy to cases not adequately classifiable by noninvasive markers. Hepatitis C virus (HCV) patients (2035) were enrolled in nine locations in Europe and the United States. The diagnostic accuracy of SAFE biopsy versus histology, which is the gold standard, was investigated. The reduction in the need for liver biopsies achieved with SAFE biopsy was also assessed. SAFE biopsy identified significant fibrosis with 90.1% accuracy (area under the receiver operating characteristic curve = 0.89; 95% confidence interval, 0.87-0.90) and reduced by 46.5% the number of liver biopsies needed. SAFE biopsy had 92.5% accuracy (area under the receiver operating characteristic curve = 0.92; 95% confidence interval, 0.89-0.94) for the detection of cirrhosis, obviating 81.5% of liver biopsies. A third algorithm identified significant fibrosis and cirrhosis simultaneously with high accuracy and a 36% reduction in the need for liver biopsy. The patient's age and body mass index influenced the performance of SAFE biopsy, which was improved with adjusted Fibrotest-Fibrosure cutoffs. Two hundred two cases (9.9%) had discordant results for significant fibrosis with SAFE biopsy versus histology, whereas 153 cases (7.5%) were discordant for cirrhosis detection; 71 of the former cases and 56 of the latter cases had a Fibroscan measurement within 2 months of histological evaluation. Fibroscan confirmed SAFE biopsy findings in 83.1% and 75%, respectively. Conclusion: SAFE biopsy is a rational and validated method for staging liver fibrosis in hepatitis C with a marked reduction in the need for liver biopsy. It is an attractive tool for large-scale screening of HCV carriers. (HEPATOLOGY 2009.)

Objective: To investigate whether interleukin-6 (IL-6) polymorphisms could be associated with the occurrence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and whether this influence could act synergistically with the gender of the patient. Methods: We studied 219 consecutive patients who underwent liver transplantation for liver cirrhosis. All total hepatectomy specimens were sectioned at intervals of 1 cm in search for suspicious focal hepatic lesions. Genotyping for the IL-6 –1363 G>T, –597 G>A, –572 G>C, –174 G>C and +2954 G>C polymorphisms was performed by restriction fragment length polymorphism. Results: A significant association was found between the presence of the A-C/A-C low producer diplotype (–597 G>A/–174 G>C loci) and absence of HCC (18/153 vs. 1/66, p < 0.02). With respect to the IL-6 A-C/A-C low producer phenotype (n = 19), females (n = 60) and males (n = 140) with the high producer phenotypes had an adjusted odds ratio for the presence of HCC of 3.74 and 14.8, respectively (p < 0.001). Conclusions: Polymorphisms of IL-6, by determining differences in its expression, are associated with HCC occurrence among patients with liver cirrhosis. The protective effect of female gender against the occurrence of HCC occurs mainly among carriers of IL-6 high producer phenotypes.

A 65-year-old man with chronic hepatitis C and no history of alcohol abuse was admitted to our liver unit for the recent development of massive ascites and presumed hepatorenal syndrome. In the preceding two weeks, he had received medical treatment for acute pancreatitis and cholecystitis. Abdominal paracentesis demonstrated a cloudy, orange peritoneal fluid, with total protein concentration 3.6 g/dl, serum-ascites albumin gradient 1.0 g/dl, and ratios of ascites-serum bilirubin and amylase approximately 8:1. Diagnostic imaging demonstrated no pancreatic pseudocysts. Ten days later, at laparotomy, acalculous perforation of the gallbladder was identified. After cholecystectomy, amylase concentration in the ascitic fluid dropped within a few days to 40% of serum values; ascites disappeared within a few weeks. We conclude that in the presence of a perforated gallbladder, pancreatobiliary reflux was responsible for this unusual combination of choleperitoneum and pancreatic ascites, which we propose to call pancreatobiliary ascites.

Liver transplantation (LT) recipients are at risk for early and delayed adrenal insufficiency for multiple reasons. Although early adrenal insufficiency is known to occur in a high proportion of recipients maintained on steroid-free immunosuppressive regimens, the prevalence and risk factors associated with delayed functional adrenal gland atrophy (FAGA) are unknown because routine evaluation for this condition is not standard practice among LT centers. We investigated a group of 87 patients (64 males) transplanted for end-stage liver disease related to different etiologies. All underwent a standard corticotropin stimulation test (CST) when, after gradual steroid tapering, they had been maintained for at least 1 week on oral prednisone at a daily dose of 5 mg. FAGA, defined by a serum cortisol concentration that, 60 minutes after corticotropin administration, did not double the baseline level and remained

End stage liver disease due to hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT) worldwide. Regretfully, infection of the graft by HCV occurs almost universally after LT, causing chronic hepatitis and early progression to cirrhosis in a significant proportion of recipients. Moreover, graft and patient survival are significantly worse in patients undergoing LT for HCV-related cirrhosis than in those transplanted for other indications. Therefore, many LT centers consider antiviral treatment with interferon and ribavirin the mainstay of managing recurrent HCV disease in LT recipients. The optimal time to start treatment is unclear. In most instances, treatment is initiated when histological evidence of disease recurrence, either at protocol or on-demand liver biopsies, is observed after LT. However, antiviral treatment initiated before LT is a potential option for some patients for two reasons: first, clearing or suppressing HCV before LT may reduce or eliminate the risk of recurrent hepatitis C in the transplanted liver and thereby improve survival; second, clearing HCV in cirrhotic patient may halt disease progression and avoid the need for transplantation. In this article, the results obtained by pre-transplant antiviral regimens administered to HCV-positive cirrhotic patients awaiting LT are discussed.

Background and Aim: Per protocol annual liver biopsy represents the gold standard in the assessment of graft fibrosis progression due to recurrent hepatitis C after liver transplantation. Non-invasive liver fibrosis tests have been proposed as surrogate markers of liver fibrosis in hepatitis C virus (HCV)-positive immune-competent patients. No data are available in the literature on the usefulness of non-invasive liver fibrosis tests in liver transplanted patients with recurrent HCV infection. Methods: A total of 102 annual per protocol liver biopsies performed in 51 consecutive HCV-positive recipients (31 men), with a follow-up period lasting up to 5 years, were included and evaluated in this study. At each time point, the following non-invasive liver fibrosis tests were calculated: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, age–platelet index, AST to platelet ratio index (APRI), Forns’ fibrosis index and Bonacini’s discriminant score. Results: In discriminating patients with histological fibrosis score >2, APRI provided the best area under the receiver operating characteristic curves (AUROC) (0.801), in comparison to the other four non-invasive liver fibrosis tests. The AUROC of APRI was better in female (0.871) than in male (0.753) recipients. Among female recipients, an APRI value >1.4 was 91% sensitive and 75% specific in detecting a staging score >2. The corresponding values among male recipients were 60% and 77%, respectively. Conclusions: Among non-invasive liver fibrosis tests, APRI has the highest diagnostic value in discriminating liver transplanted patients with progression to significant liver fibrosis, although its accuracy is influenced by recipient sex.

Background/Aims: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, being a putative steatogenic factor, may promote liver fibrosis progression in patients with chronic hepatitis C. This study aimed to verify the role of recipient MTHFR polymorphism in favouring graft fibrosis progression in patients with recurrent HCV after orthotopic liver transplantation (OLT). Methods: We studied 63 such patients, followed for >1 year. MTHFR allelic variants were determined by a polymerase chain reaction/restriction fragment length polymorphism method. Results: Recipients carrying the TT genotype had more frequently, 1-year post-OLT, homocysteine serum levels >23 μmol/L (P 180 mg/dL (P 2 was performed by stratifying the recipients as follows: (a) patients with donor age ≤45 years, (b) patients with donor age >45 and C/* genotype, and (c) patients with donor age >45 years and TT genotype. A significant linear trend was observed, with increasing frequencies as follows: (a) 8/37, (b) 10/19 and (c) 6/7 (P=0.0005). Conclusion: The MTHFR C677T polymorphism may play a role in influencing liver fibrosis progression in patients with recurrent hepatitis C, in conjunction with donor age, but not via steatosis promotion.

Experimental evidence and clinical studies suggest that the renin-angiotensin system and its inhibitors may play a role in regulating the mechanisms of liver fibrosis development. The present study aimed to verify whether carriage of specific angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) allelic variants, modulating angiotensin II generation, could affect the outcome of recurrent hepatitis C after liver transplantation, via several metabolic pathways.Forty-five (29 men) recipients, with a median histological follow-up of 60 months after orthotopic liver transplantation (OLT), were studied. ACE gene I/D polymorphism was assessed by means of a polymerase chain reaction procedure. Fibrosis progression was evaluated annually during the follow-up.Weight gain 1 year post-OLT (defined as an increase in body mass index, BMI, of0.5 kg/m(2)) was significantly more common among D/ carriers (22/22 vs. 16/23, P0.005); patients who 1 year after OLT had an increase in their BMI value of0.5 kg/m(2) more frequently had a triglycerides/cholesterol ratio ofor= 0.7 (16/22 vs. 8/23, chi-squared test P0.02). This association was stronger in men. Female D/D homozygotes had the highest probability of showing significant liver fibrosis (7/10) in comparison with men (11/29) and I/ women (1/6) (P0.01).In patients with recurrent hepatitis C, carriers of the D allele appeared to gain more weight after liver transplantation, and in male liver recipients, the D allele was associated with a peculiar lipid profile that was associated with a slower rate of allograft fibrosis progression. Among female recipients, carriage of the D allele may favor more severe allograft fibrosis.

Henoch–Schonlein purpura (HSP) is a small-vessel vasculitis, characterized by arthritis, gastrointestinal involvement, renal disease, and non-thrombocytopaenic palpable purpura. Typically, HSP affe...

Background: The red cell distribution width is a biomarker of early mortality across various disease states. Aim: To verify whether it may refine estimates of survival in hepatocellular carcinoma. Methods: The red cell distribution width measured at diagnosis was analyzed in relationship to mortality by any cause both in a retrospective training cohort (N = 208), and in an independent prospectively collected validation cohort (N = 106) of patients with hepatocellular carcinoma. Based on Cox proportional hazards modelling, a prognostic index was validated. Results: In the training and the validation cohort, median survival time was respectively 1026 and 868 days in patients with red cell distribution width ≤14.6%, vs. 282 and 340 days in patients with red cell distribution width >14.6%; the corresponding hazard ratios were 0.43 (95% CI: 0.31–0.60), p < 0.0001 and 0.28 (95% CI: 0.17–0.47), p < 0.0001. At multivariate analysis, the red cell distribution width remained an independent predictor of survival (p < 0.001) in a Cox model including other widely accepted prognostic factors. Applying to the validation dataset the prognostic index derived from the training dataset, the ability of the model to discriminate the survival probabilities of patients was confirmed (Harrell’s C = 0.769). Conclusions: The red cell distribution width is a novel, reproducible, prospectively validated predictor of survival in patients with hepatocellular carcinoma.

Catecholamine excess along with an exaggerated sympathetic stimulation appears to play a major role in the pathophysiological mechanism of tako-tsubo cardiomyopathy (TTC), which mimics acute ST-elevation myocardial infarction (STEMI). The aim of the present study was to investigate differences in the distribution of allelic variants of β1- and β2-adrenoceptors between TTC and anterior STEMI patients compared to normal subjects.β1- and/or β2-adrenoceptor polymorphisms in 97 patients with TTC (92 females, 96%; mean age 66.8±11.6years; range 35 to 87years) were compared with 81 patients with anterior STEMI (77 females, 95%; mean age 72.5±12.8years; range 32 to 96years) and 101 controls (95 females, 94%; mean age 62.3±10.4years; range 44 to 92years). Differences in genotype frequencies were assessed using the Pearson χ(2) test. β1-Adrenoceptor (Gly389Arg) and β2-adrenoceptor (Arg16Gly and Gln27Glu) genotype frequencies were significantly different among groups (p0.001, p=0.024, p=0.008, respectively). However, differences did not achieve statistical significance when TTC and anterior STEMI patients were compared by post-hoc analysis. The cardiovascular risk factor profile was worse in anterior STEMI patients, who more often had a history of systemic arterial hypertension, diabetes and coronary artery disease.In a large TTC cohort compared with anterior STEMI patients, β-adrenoceptor polymorphisms were similar. However, the cardiovascular risk factor profile was different between the two groups. β-Adrenoceptor polymorphisms in TTC patients differed from normal subjects.

Imatinib mesilate is a tyrosine kinase inhibitor that has been shown to be highly effective in the treatment of malignancies, such as chronic myeloid leukaemia and gastrointestinal stromal tumours that are characterised by specific molecular defects towards which this drug is targeted. The authors briefly review selected preclinical and clinical data concerning the use of imatinib in some common solid tumour types, concluding that the biological and clinical impact still needs to be further elucidated. Imatinib represents a promising therapeutic option with far less toxicity than traditional approaches, although integrated, multimodality approaches, including surgery, will remain of value in the era of molecularly targeted therapy.

Therapy of hepatitis C virus (HCV) infection may prevent progression to cirrhosis, hepatocellular carcinoma and end-stage liver disease. The cornerstone of treatment has long been standard IFN-alpha, the use of which was associated with a sustained biochemical and viral response in only a small proportion of patients. More recently, the success of interferon-based regimens has substantially improved due to the combination with the guanosine analogue ribavirin and to the advent of pegylated interferon formulations. However, even the most up-to-date regimens fail to cure the infection in many cases and are limited by side effects and high costs. A better understanding of the HCV genomic organisation, the elucidation of the three-dimensional structures of virally encoded enzymes and the recent development of a HCV-replicon system in human hepatoma (Huh-7) cells have led to significant advances in the development of new antiviral compounds, many of which are under evaluation in clinical trials. The aim of this review is to trace a brief overview of the progress made by interferon-based treatments for hepatitis C since their introduction in the early 1990s, and to highlight the results of recent clinical studies concerning new and emerging drugs.