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There is an established correlation between the PNPLA3 rs738409 C > G single nucleotide polymorphism (SNP) and hepatic steatosis and fibrosis in hepatitis C virus (HCV) infected patients. However not all data is convergent regarding the exact impact of this SNP on the pattern of disease progression in different clinical settings. In this study, we aimed to further bridge the knowledge gap on this topic by investigating the role of the G allele in promoting steatosis, fibrosis and disease progression in relation to other metabolic and anthropometric host factors. Two hundred and fifty consecutive patients, previously diagnosed with chronic hepatitis C (CHC) underwent liver biopsy. Histology was assessed using the Metavir scoring system. Transient elastography was used for follow-up. Ninety-eight patients were genotyped for PNPLA3 rs738409 and followed up for fibrosis progression. PNPLA3 rs738409[G] allele was significantly correlated with severe steatosis (P = 0.04), severe fibrosis at the time of enrollment (P = 0.0005) and fibrosis progression with an OR of 10.31 (95% CI 1.06 - 99.59, P = 0.04), after a mean follow-up time of 62.85 (95%CI: 52.21 - 76.15) months. Severe steatosis at the time of enrollment had an OR of 11.02 (95% CI 1.48 - 82.09, P = 0.01) for the association with fibrosis progression. The HOMA-IR index was also positively correlated with severe fibrosis (P = 0.03) and fibrosis progression on univariate analysis (P = 0.02). PNPLA3 rs738409[G] allele is a reliable predictor for steatosis and fibrosis in CHC. The presence of G allele, along with severe steatosis and insulin resistance are significant predictors for fibrosis progression.

Background & Objectives: One of the multiple factors contributing to virological response in chronic hepatitis C (CHC) is interferon-gamma-inducible protein-10 (IP-10). Its level reflects the status of interferon-stimulated genes, which in turn is associated with virological response to antiviral therapy. The aim of this study was to evaluate the role of serum IP-10 levels on sustained virological response (SVR) and the association of this parameter with insulin resistance (IR) and liver histology., Methods: Two hundred and three consecutive biopsy proven CHC patients were included in the study. Serum levels of IP-10 were determined using ELISA method. IR was evaluated by homeostasis model assessment-IR (HOMA-IR). Histological features were assessed invasively by liver biopsy and noninvasively using FibroTest, ActiTest and SteatoTest. Predictive factors for SVR and their interrelations were assessed., Results: A cut-off value for IP-10 of 392 pg/ml was obtained to discriminate between responders and non-responders. SVR was obtained in 107 patients (52.70%). Area under the receiver operating characteristic curve for SVR was 0.875 with a sensitivity of 91.6 per cent, specificity 74.7 per cent, positive predictive value 80.3 per cent and negative predictive value 88.7 per cent. Higher values of IP-10 were associated with increasing stages of fibrosis (P<0.01) and higher grades of inflammation (P=0.02, P=0.07) assessed morphologically and noninvasively through FibroTest and ActiTest. Significant steatosis and IR were also associated with increased levels of IP-10 (P=0.01 and P=0.02). In multivariate analysis, IP-10 levels and fibrosis stages were independently associated with SVR., Interpretation & Conclusions: Our findings showed that the assessment of serum IP-10 level could be a predictive factor for SVR and it was associated with fibrosis, necroinflammatory activity, significant steatosis and IR in patients with chronic HCV infection.

Background: Non-invasive methods for the assessment of liver fibrosis are accurate in staging chronic liver diseases before treatment., Aim: To prospectively assess liver fibrosis in chronic hepatitis C (CHC) in patients treated vs untreated, using non-invasive methods., Method: 224 patients with CHC were included in the study: 179 received antiviral treatment for 48 weeks, and 45 patients received no antiviral therapy. All patients underwent liver biopsy at baseline and were also evaluated by simple biological scores (APRI, HAPRI, Forns, Bonacini, Lok) and transient elastography (TE). The progression of fibrosis was non-invasively assessed over a period of 72 weeks., Results: Fibrosis decreased significantly in patients who gained sustained virological response (SVR). A significant decrease of fibrosis was also observed in all treated patients, irrespective of SVR when using APRI, HAPRI and Bonacini scores (p=0.001, 0.009 and 0.02). Untreated patients yielded constant values of fibrosis or a slight increase in follow-up. Patients with Lok score and stiffness predictive for cirrhosis had a decreasing trend of fibrosis (p=0.03 for Lok and 0.05 for TE), but persisting in the cirrhosis domain. Of the non responders, those who gained biological response demonstrated improvement of fibrosis assessed by APRI and TE., Conclusion: The prospective follow-up of liver fibrosis assessed by simple biological scores and TE in patients with CHC revealed a downstaging of fibrosis in treated patients and especially in those who gained SVR.

Non-invasive biochemical markers are useful to distinguish between nonalcoholic steatohepatitis (NASH) and simple steatosis. The aim of this study was to test the diagnostic value of a panel of biomarkers derived from the pathophysiological events involved in the development of NASH. A total of 79 patients: 20 not-NASH and 59 NASH were included in the study. Definitive NASH was defined according to Kleiner's classification. In all subjects, parameters of the metabolic syndrome, insulin resistance (HOMA-IR), adiponectin, interleukin-6 (IL-6) and total cytokeratin-18 (M65 antigen) were determined. Univariate and multivariate analysis were used to identify independent predictors of NASH. In multivariate analysis three markers were independently predictors of NASH: adiponectin, IL-6 and M65 levels. In decreasing order, the independent predictors of NASH (NAS≥5) were M65 with an AUROC of 0.791, IL-6 with an AUROC of 0.727 and adiponectin with an AUROC of 0.709. The combination of two biomarkers yelded an AUROC of 0.828 for M65 and IL-6, 0.841 for adiponectin and M65 and 0.852 for adiponectin and IL-6. The best value was obtained by triple combination: adiponectin, M65 and IL-6 with and AUROC of 0.903, Sp=85.7% (PPV=94.2%) and Se=84.5% (NPV=66.7%). In conclusion, a novel pathophysiological - based panel of biomarkers combining total CK-18, IL-6 and adiponectin may be useful to predict NASH.

Background: The prediction of fibrosis is an essential part of the assessment and management of patients with chronic liver disease. Non-invasive tests (NITs) have a number of advantages over the traditional standard of fibrosis assessment by liver biopsy, including safety, cost-effectiveness, and widespread accessibility., Objectives: The aim of this study was to determine the accuracy of certain biomarkers and transient elastography (TE) alone or in combination to predict the stage of liver fibrosis in chronic hepatitis C (CHC). Also, we examined whether the combination of certain biomarkers and TE could increase the diagnostic accuracy of liver fibrosis assessment., Patients and Method: A total of 446 patients who were previously diagnosed with CHC were included in the study. In the study group, 6 blood-based scores (APRI, Forns, Fib-4, Hepascore, FibroTest, and Fibrometer) were calculated, and TE was performed to validate the stage of fibrosis, compared with liver biopsy (LB) as the standard., Results: Significant fibrosis (F ≥ 2) was predicted with an AUROC of 0.727, 0.680, 0.714, 0.778, 0.688, 0.797, and 0.751 for the APRI, Forns, Fib-4, FibroTest, Hepascore, and Fibrometer scores and TE (Fibroscan), respectively. Severe fibrosis (F ≥ 3) was predicted, with AUROCs ranging between 0.705 and 0.811 for Hepascore and Fibrometer, respectively. Of the biomarkers, Fibrometer had the highest AUROC value in predicting both significant and severe fibrosis. The combination of APRI or FIB-4 with Fibrometer increased the diagnostic accuracy for significant fibrosis (from 69.07 to 82.27 for APRI, P = 0.001 and from 57.74 to 81.33, P = 0.001 for Fib-4). Combining APRI or Fib-4 with TE also increased the diagnostic accuracy (from 69.07 to 80.70%, P = 0.001 for APRI and from 57.74 to 81.33%, P = 0.001 for Fib-4) for significant fibrosis. The association that included Fibrotest was also reliable for the improvement of diagnostic accuracy. These combinations were more accurate or the assessment of severe fibrosis., Conclusions: The synchronous association between a simple, inexpensive score and a complex but expensive score or TE increases the diagnostic accuracy of non-invasive methods for the assessment of liver fibrosis stage.

Background/aim: To present clinical and genetic characteristics of all Romanian patients with Gaucher disease type 1, in whom specific diagnosis has been confirmed by enzymatic and molecular methods and to analyze their outcome with and without enzymatic replacement therapy (ERT)., Patients, Methods: There are fifty patients (F/M - 1.63/1) with Gaucher disease type 1. Clinical status, haemoglobin, thrombocytes, hepatic/splenic volume, bone mineral density and severity score were assessed at baseline and every six months thereafter. Thirty-nine patients (78%) received imiglucerase (44.4+/-13.6 U/kg/2 weeks) for 3.1+/-1.4 years., Results: Based on general prevalence data, our group represents 22.7% of the expected total number of patients with Gaucher disease type 1 in Romania. Mean age was 15.5 years at clinical onset and 28.9 years at confirmation of diagnosis. The genotype N370S/L444P was frequent in our group (35.9% of alleles). Anaemia, thrombocytopenia, splenomegaly and bone disease were present at 38%, 70%, 100% and 84%, respectively. Mean values for haemoglobin, thrombocytes, hepatic volume and chitotriosidase normalized after 0.5, 1.5, 2.5 and 3 years of ERT, respectively. Splenomegaly regressed from 14.4 x N (normal) to 3.06 x N over four years of treatment. Bone disease was ameliorated under ERT, yet bone mineral density worsened in patients treated with 30 U/kg/2 weeks., Conclusions: The genotype N370S/L444P is frequent in our patients, in line with the severe phenotypes. ERT improved haematological parameters and visceromegaly, without a clear benefit for bone mineral density. To attain therapeutic goals, an early treatment start with optimal dosage is mandatory., (Copyright 2009 Elsevier B.V. All rights reserved.)

Aims: To assess insulin resistance and adiponectin profile in patients with chronic hepatitis C (CHC), according to the presence or absence of metabolic syndrome (MS)., Patients and Methods: One hundred and fifty-two patients with histologically proven CHC, genotype I were prospectively studied. Parameters of MS according to the IDF criteria were evaluated. Insulin resistance was established by homeostasis model assessment (HOMA-IR]. An index > or = 2.0 was designated as IR and > or = 4 as prediabetic state. Serum adiponectin levels were measured by ELISA:, Results: MS was found in 61.48% of cases. HOMA-IR was significantly higher in patients with CHC and MS vs those without MS (7.88 +/- 1.11 vs 4.29 +/- 0.5, p=0.023]. Adiponectin levels had an inverse behaviour (9,946.1 +/- 5,811 ng/ml vs 13,215.5 +/- 815.5 ng/ml, p< 0.001]. By multiple linear regression analysis the independent predictors associated with HOMA-IR > or = 4 in patients with CHC and MS were visceral obesity, adiponectin levels, activity and degree of steatosis. Only visceral obesity and HOMA-IR were independently associated with adiponectin. A significant negative correlation was established between adiponectin and insulin (r = -0.169, p=0.003] and between adiponectin and HOMA-IR (r = -0.188, p=0.02]., Conclusions: CHC with MS was associated with a higher insulin resistance and lower adiponectin level. Adiponectin level and insulin resistance were significantly correlated.

Aim: To assess the diagnostic value of FibroTest to discriminate between insignificant and significant fibrosis in order to avoid the liver biopsy currently used for selection of chronic hepatitis C patients eligible for antiviral therapy., Patients and Methods: A retrospective study was carried out in 206 chronic hepatitis C patients with liver biopsy performed before starting antiviral therapy and concomitant serum stored at -80 degrees C. Liver fibrosis was evaluated according to the METAVIR scoring system on a scale of F0 to F4. Biochemical markers assessed were: alpha 2 macroglobulin (alpha 2-MG), apolipoprotein A1 (Apo-A1), haptoglobin (Hapto), gamma-glutamyltransferase (GGT), total bilirubin (TB). The FibroTest score was computed after adjusting for age and gender. Predictive values and ROC curves were used to assess the accuracy of FibroTest results., Results: Alpha 2-MG, apo-A1, Hapto and gender were independent predictors for significant fibrosis. For FibroTest the observed area under ROC (ObAUROC) for the discrimination between minimal or no fibrosis (F0-F1) and significant fibrosis (F2-F4) was 0.782 (+/- 95 CI: 0.716-0.847) for a cutoff value 0.47. The sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of the FibroTest to differentiate significant from insignificant fibrosis were 80.2; 63.2; 78.9 and 65.8, respectively. The adjusted AUROC (AdAUROC) according to the prevalence of each individual stage of fibrosis was 0.856., Conclusion: FibroTest could be an alternative to biopsy in most patients with chronic hepatitis C. It requires a strict adherence and observance of the technical recommendations for the assays of biochemical markers in order to avoid analytical variability.

The understanding of pathogenesis of acute and chronic pancreatitis has benefited from the progress made in genetic investigations. The discoveries of the gain of function mutations of cationic trypsinogen gene (PRSS1) and the loss of function mutations of pancreatic secretory trypsin inhibitor (SPINK 1) or other potential defects in genes that regulate pancreatic secretory function or modulate inflammatory response to pancreatic injury has changed our current concepts on the pathogenesis of pancreatitis. Genetic factors play an important role in the susceptibility to pancreatic injury, severity and evolution of inflammatory process, leading in some cases to chronic inflammation and/or fibrosis. Acute pancreatitis is viewed as an event and chronic pancreatitis as a process, sequentially linked, reflecting a complex interaction between genetic and environmental factors.