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Background and Aim Chronic hepatitis C (CHC) has been associated with lymphoproliferative disorders (LPD) such as mixed cryoglobulinemia syndrome (MCS), monoclonal gammopathy of undetermined significance (MGUS), and B-cell non-Hodgkin lymphoma (B-NHL). The aim of the present study is to assess MCS, MGUS, and B-NHL prevalence in a cohort of CHC-infected patients and to evaluate the association of demographic, clinical, and virologic factors with the presence of LPDs. Methods A total of 121 CHC patients with LPDs (50 M, 71 F; mean age 61.5 ± 11.8) and 130 CHC patients without extrahepatic manifestations (60 M, 70 F; mean age 60.4 ± 9.2) were retrospectively enrolled from a cohort of 1313 CHC patients between January 2006 and December 2013. Patients with LPDs included: 25 patients with MCS (9 M, 16 F; mean age 60.2 ± 1.4), 55 patients with MGUS (18 M, 37 F; mean age 61.3 ± 12.1), and 41 patients with B-NHL (23 M, 18F; mean age 62.5 ± 11.0) Results Patients with MCS (25/1313; 1.9%), MGUS (55/1313; 4.2%), and B-LNH (41/1313; 3.1%) did not differ in age, severity of liver disease, HCV genotype, and response to antiviral therapy. Using multivariate logistic regression analysis, a positive association was found between the presence of cirrhosis and MGUS (odds ratio [OR] = 2.8924, 95% confidence interval [CI] 1.2693–6.5909; P = 0.012) and between cirrhosis and B-NHL (OR = 3.9407, 95%CI 1.7226–9.0153; P = 0.001), whereas no association with MCS diagnosis emerged. Conclusion Despite the pathogenetic mechanism of HCV-associated LPDs is still unclear, cirrhosis is an additional risk factor for the development of lymphoproliferative disorders in patients with chronic HCV infection.

The presence of non-organ-specific (NOSA) and anti-endothelial antibodies (AECAs) and the onset of rejection in relation to cytomegalovirus (CMV) infection was investigated in 96 renal transplant recipients: 48 CMV pp65-antigenemia-negative (group 1) and 48 positive (group 2). The presence of autoantibodies (autoAbs) was evaluated before and following renal transplantation (first three months) by indirect immunofluorescence. Before transplantation, none of the patients was positive to AECAs, while eight (8.3%) were positive to NOSAs. Post-transplantation, AECA were found in none of patients from group 1 vs. 15/48 (31.2%) from group 2 (p

Background The combination of non-invasive markers for the detection of fibrosis in patients with chronic liver diseases is still a matter of debate. Aims To test the performance of cytokeratin18-Aspartate396 alone or in combination with transient elastography as a marker of fibrosis, compared to liver biopsy as gold standard. Methods In 259 prospectively enrolled patients with chronic liver diseases, clinical, biochemical, and histological features were assessed. Serum cytokeratin18-Aspartate396 and Fibroscan were performed within 6 months prior to liver biopsy. Results Cytokeratin18-Aspartate396 levels predicted both significant and advanced fibrosis in non-alcoholic fatty liver disease group, correctly identifying 83.7% and 80.8% of cases, respectively. Liver stiffness performed best in predicting severe fibrosis in patients with chronic viral infection, correctly identifying 78.7% of chronic hepatitis B and 88.6% of chronic hepatitis C subjects. The combination of cytokeratin18-Aspartate396 and liver stiffness improved their diagnostic performance for the detection of significant and advanced fibrosis in non-alcoholic fatty liver disease group, only (sensitivity = 78.3%, specificity = 90.7%; sensitivity = 91.7%, specificity = 71.6%, respectively). Conclusion Cytokeratin18-Aspartate396 and liver stiffness can improve the non-invasive prediction of significant and advanced fibrosis in patients with non-alcoholic fatty liver disease, while in hepatitis B and C virus infected patients their combined use had no advantage over the diagnostic accuracy of transient elastography alone.

In the clinical setting may be difficult the discrimination of patients with inflammatory bowel diseases from those with functional intestinal disorders due to the overlapping and non-specific symptoms, such as abdominal pain and altered bowel habit. Several blood markers currently help clinicians in the management of these patients, but the low specificity makes them unreliable for the detection and monitoring of the disease activity. The gold standard to establish a diagnosis of organic bowel disease is colonoscopy with multiple biopsies, but is an invasive and costly procedure. In the last decade, fecal calprotectin (FC), a cytosolic protein mainly found in neutrophil granulocytes, has been proposed as a surrogate marker of intestinal mucosa inflammation and has been associated with several gastrointestinal disorders. We recently addressed FC ability in distinguish inflammatory from functional disorders, taking into consideration different pathological intestinal conditions. In this research highlight we provide a brief review on FC role as a biomarker of intestinal inflammation discussing the clinical applications.

Chronic hepatitis C (CHC) has been associated with lymphoproliferative disorders (LPD) such as mixed cryoglobulinemia syndrome (MCS), monoclonal gammopathy of undetermined significance (MGUS), and B-cell non-Hodgkin lymphoma (B-NHL). The aim of the present study is to assess MCS, MGUS, and B-NHL prevalence in a cohort of CHC-infected patients and to evaluate the association of demographic, clinical, and virologic factors with the presence of LPDs.A total of 121 CHC patients with LPDs (50 M, 71 F; mean age 61.5 ± 11.8) and 130 CHC patients without extrahepatic manifestations (60 M, 70 F; mean age 60.4 ± 9.2) were retrospectively enrolled from a cohort of 1313 CHC patients between January 2006 and December 2013. Patients with LPDs included: 25 patients with MCS (9 M, 16 F; mean age 60.2 ± 1.4), 55 patients with MGUS (18 M, 37 F; mean age 61.3 ± 12.1), and 41 patients with B-NHL (23 M, 18F; mean age 62.5 ± 11.0) RESULTS: Patients with MCS (25/1313; 1.9%), MGUS (55/1313; 4.2%), and B-LNH (41/1313; 3.1%) did not differ in age, severity of liver disease, HCV genotype, and response to antiviral therapy. Using multivariate logistic regression analysis, a positive association was found between the presence of cirrhosis and MGUS (odds ratio [OR] = 2.8924, 95% confidence interval [CI] 1.2693-6.5909; P = 0.012) and between cirrhosis and B-NHL (OR = 3.9407, 95% CI 1.7226-9.0153; P = 0.001), whereas no association with MCS diagnosis emerged.Despite the pathogenetic mechanism of HCV-associated LPDs is still unclear, cirrhosis is an additional risk factor for the development of lymphoproliferative disorders in patients with chronic HCV infection.

The management of patients with chronic liver disease (CLD) requires an accurate definition of the staging and grading, as the latter is related to the progression of liver fibrosis. Albeit liver biopsy (LB) is an invasive procedure with possible complications, it is currently the "gold standard" for the assessment of hepatic fibrosis. Over the past decade, several noninvasive approaches have been proposed as surrogates in the evaluation of liver fibrosis. These include serum direct and indirect markers of fibrosis linked, respectively, to fibrogenesis and hepatic function, and instrumental techniques, which measure liver stiffness, a parameter directly correlated with liver fibrosis. Although accuracy of noninvasive methods was initially investigated in chronic hepatitis C, there are now increasing data referred to their application in other CLDs. While in specific settings, there is still need for LB, noninvasive methods have an increasing and crucial role in clinical practice to monitor fibrosis progression in patients with CLD. The aim of this review is to present the current status of knowledge in this new exciting field and to highlight the key messages useful for clinicians.

AIM: To clarify the association of interleukin-28B (IL28B) single nucleotide polymorphisms (SNPs) with hepatitis C virus (HCV) viremia changes for assessment of interferon (IFN) response. METHODS: A cohort of 118 Caucasian treatment-naive HCV-G1 infected patients, treated with pegylated-IFN alpha 2a or 2b associated with ribavirin (53 responders, 65 non-responders) during the period 2010-2012, were genotyped for IL28B SNPs rs12979860 C>T and rs8099917 T>G. Genotyping was performed by real-time allelic discrimination assay. Serum HCV RNA levels were assayed at 2, 4, 12, 24 and 48 wk during therapy. Correlation between IL28B genotypes and serum HCV RNA kinetics was investigated. Multivariable logistic regression analysis was performed to identify predictors of null-response. RESULTS: Twenty-six out of 118 patients (22%) had no HCV RNA decline ≥ 1 log IU/mL at therapy week 4 (null-responders). IL28B genotype was rs8099917 (G*)/rs1297860(**) in 21/26 (80%) of null-responder patients. Using multivariate analysis, it was shown that the presence of the rs8099917 G allele was the best predictor of null-response (OR = 7.9, 95%CI: 1.99-31.18). The presence of at least one favorable genotype showed a positive predictive value of above 90% for HCV RNA reduction ≥ log at week 4. Analysis of the HCV RNA kinetics during 12 wk of therapy in patients with IL28B rs12979860 CT heterozygosis (n = 73), according to their rs8099917 status, showed that the viremia reduction was significantly different in patients carrying the rs8099917 G allele compared to those with favorable homozygosis. CONCLUSION: Our findings emphasize the association of the IL28B rs8099917 G allele with HCV. Genotyping for both IL28B SNPs is useful in clinical practice for thorough patient risk stratification based on IFN responsiveness.

The clinical pictures of functional gastrointestinal disorders and inflammatory diseases can be quite similar leading to inappropriate and expensive investigations. Objective. To investigate fecal calprotectin (FC) diagnostic performance in different gastrointestinal conditions.Stool specimens of 66 outpatients referred for colonoscopy were collected for further FC determination. Diagnostic accuracy was assessed by the area under the curve (AUC). Sensitivity (Se), specificity (Sp), positive (PPV), and negative predictive values (NPV) were calculated according to the presence of inflammation and the main final diagnosis.Histological inflammation was found in 45 (68%) patients: 24 had a diagnosis of inflammatory bowel disease (IBD) while 21 reported miscellaneous conditions (5 microscopic colitis, 2 eosinophilic colitis, and 14 nonspecific chronic colitis). The diagnosis in the 21 (32%) patients without inflammation was irritable bowel syndrome (IBS). Median FC values were 268 µg/g (95% CI, 151-343) and 49 µg/g (95% CI, 23-101) in patients with and without inflammation, respectively (p = 0.0001). AUC value of FC was 0.811 (Se = 68.9%, Sp = 71.4%, PPV = 83.8%, and NPV = 56.3% with a cutoff value of 100 µg/g) for discriminating between patients with and without inflammation and 0.931 (Se = 87.5%, Sp = 90.5%, PPV = 91.3%, and NPV = 86.4% with a cutoff value of 150 µg/g) for discriminating between patients with IBS and IBD. Using the cutoff value recommended by the manufacturer (50 µg/g), we found Se =100%, Sp =52.4%, PPV =70.6%, and NPV =100% for the diagnosis of IBD.FC appears to be a reliable noninvasive biomarker of intestinal inflammation useful to improve the appropriateness of colonoscopy requests.

Background. In the management of chronic hepatitis C (CHC) patients, liver biopsy is the gold standard for liver fibrosis assessment despite some technical limits and risks. Non-invasive approaches have been proposed as alternative methods to evaluate structural liver damage. Aim. To investigate the diagnostic accuracy of transient elastography, 13C-aminopyrine breath test ( 13 C-ABT), serum hyaluronic acid (HA) and cytokeratin 18 Asp396 fragment (CK-18) as non-invasive methods of liver fibrosis assessment ad their correlation to METAVIR score. Material and methods. In a cohort of 57 CHC patients, liver stiffness, cumulative percentage of administered dose of 13C-aminopyrine at 120 min, serum HA and serum CK-18 concentration were determined. Diagnostic accuracy in detecting significant fibrosis (F ≥ 2), severe fibrosis (F ≥ 3) and cirrhosis (F = 4) was assessed by the area under the receiver operating characteristic curve. Results. Liver fibrosis score showed a strong correlation with liver stiffness (r = 0.667; p < 0.0001) and a significant inverse correlation with 13C-ABT results (r = -0.418; p = 0.0012). A weaker correlation was found with CK18 (r = 0.329; p = 0.0126) and no correlation with HA. Areas under the curve of elastography, 13C-ABT, HA and CK18 were: 0.98, 0.75, 0.69, 0.64, respectively, for F ≥ 2; 0.97, 0.69, 0.80, 0.66, respectively, for F ≥ 3; 0.95, 0.64, 0.70, 0.56, respectively, for F = 4. Conclusion. Elastography has the best diagnostic accuracy for the assessment of the degree of liver fibrosis in CHC patients. Its application can provide an alternative useful tool for monitoring the disease evolution.

Background. A pathogenic role for polyomavirus BK in systemic lupus erythematosus (SLE) has been proposed, however no study evaluated the occurrence of BK replication in renal transplant recipients according to the underlying disease leading to transplantation and its potential impact. Methods. The occurrence of BK reactivation was serially evaluated in 468 renal transplant recipients, including 11 patients with SLE as underlying disease (overall, 2370 serum and 2370 urine specimens; 65 from SLE patients). Results. Considering the overall occurrence of viral reactivation (viremia and/or viruria), 26/65 (40%) specimens were positive in four SLE patients (36.3%) versus 331/2143 (15.4%) in 130/227 (57.3%) non-SLE patients. A patient transplanted for class III lupus nephritis evidenced sustained BK viremia and viruria (with viremia values potentially indicative of polyomavirus-associated nephropathy) in the absence of clinical features of renal dysfunction or recurrence of lupus nephritis. Conclusions. Further studies on larger populations and for a longer follow-up should be required to evaluate the impact of BKV reactivation in renal transplant patients with SLE as underlying disease, as well as the potential therapeutic implications.

Introduction. Reactivation of polyomavirus BK in kidney transplant recipients has been associated to the development of nephropathy (polyomavirus-associated nephropathy, PVAN), possibly leading to the loss of the transplanted organ. Immunosuppression is the condicio sine qua non for the onset of PVAN; however, a lower incidence of BK viremia has been reported with low-level tacrolimus based immunosuppressive protocols in comparison to cyclosporine A.Aim of this study was to compare the two immunosuppressive protocols. Methods. Virological monitoring of BK was performed in 468 consecutive renal transplant patients over a period of 3 years (2370 urine e 2370 serum specimens): in particular, 1780 specimens from 362 patients treated with tacrolimus and 590 from 106 treated with cyclosporine A. Results. BK viremia was evidenced in 124 (7.0%) and 12 (2.0%) specimens from 40 (11.0%) and 11 (10.4%) patients treated with tacrolimus and cyclosporine A, respectively; similarly, BK viruria in 289 (16.2%) and 58 (9.8%) specimens from 67 (18.5%) and 27 (25.5%) patients, being the difference of incidence highly significant (p

A B S T R A C T Background: Occult hepatitis B virus infection (OBI) is defined as the presence of hepati- tis B virus (HBV) DNA in the liver and/or in the serum of patients with negative results of hepatitis B s antigen (HBsAg) test with or without serological markers of previous viral exposure. The impact of OBI in patients with chronic hepatitis C (CHC) is still unclear. Objectives: The Aim of this study was to assess OBI prevalence and its potential implica- tions on treatment outcome in a cohort of patients with CHC underwent standard anti- viral therapy. Patients and Methods: Baseline serum samples from 137 HBsAg-negative CHC patients treated with pegylated-interferon and ribavirin (73 Responders/74 Non Responders), were retrospectively analyzed for HBV status. Results: Seventy-three patients (53.3%) showed markers of previous exposure to HBV. HBV DNA was detected in 2 of 137 serum samples (1.5%), both carrying HBV antibodies. Liver biopsies and post-therapy sera were available for 35 patients (12 Responders/23 Non Responders). HBV DNA sequences were found in 13 of 35 specimens (37.1%), all of patients with HBV DNA negativity in basal and post-therapy serum samples. Among OBI-positive patients, 5 (38.5%) carried serological markers of HBV infection. Regarding therapy out- come, in the OBI-positive group there were 5 of 13 (38.5%) sustained virological respond- ers (SVR) compared to 7 of 22 (31.8%) in the OBI-negative one. Conclusions: Despite the high prevalence rate of liver HBV DNA in patients with CHC, SVR was not affected by occult HBV infection.

This study was carried out on 33 patients who were sero-positive for liver-kidney microsomal antibodies (LKM) in order to examine clinical features and the presence of underlying hepatitis C virus infection. Twenty-four sera were positive for antibodies against HCV (anti-HCV) as detected by enzyme immunoassay and confirmed by recombinant immunoblot assay. These patients had chronic liver disease and the majority of those treated with interferon responded favourably. Three of the nine anti-HCV-negative patients had idiopathic chronic hepatitis and two responded favourably to steroids. Two patients were diagnosed as having toxic hepatitis and the other four had various extrahepatic disorders without evidence of liver involvement. The immunoblotting analysis showed reactivity with a 50 kDa microsomal protein which presumably corresponded to cytochrome P-450 db1 both in anti-HCV-positive and -negative sera. In addition a few anti-HCV-positive sera also reacted with a 35 kDa microsomal antigen. Autoimmune markers different from LKM were absent in both groups. The high prevalence of antibodies to the hepatitis C virus among LKM-positive sera confirms that this infection plays a role in forms of chronic hepatitis that had previously been labelled autoimmune. In patients with LKM the presence of anti-HCV may help to forecast a therapeutic response to interferon, while its absence may forecast response to steroid therapy.

Following primary infection, the polyomavirus BK remains latent in the urinary tract e peripheral blood cells. Reactivation may occur spontaneously in healthy subjects and in immunocompromised conditions. BKV reactivation may determine urinary shedding of infected urothelial cells, hemorrhagic cystitis (particularly in bone marrow transplant recipients), and nephropathy in kidney graft recipients. Moreover, a possible role for BKV in the pathogenesis of systemic lupus erythematosus (SLE) has been hypothesised. SLE is characterised by production of autoantibodies, in particular anti-double stranded (ds)-DNA antibodies. The induction of anti-dsDNA antibodies by BKV has been described in experimental animals and during naturally acquired infection in man. Therefore, it has been proposed that the BKV large T-antigen-chromatin complex may function as a hapten-carrier model with subsequent production of anti-dsDNA antibodies.Aim of this study was to evaluate the relation between BKV and autoimmunity in renal transplant recipients by determining the prevalence of non-organ-specific antibodies (NOSA) by indirect immunofluorescence on serum samples obtained from 95 renal transplant recipients during post-transplantation follow-up. BKV infection was evaluated by competitive-quantitative PCR. NOSA were present in 25/95 patients: 18 ANA and 6 SMA, one patient both ANA and SMA. BKV-DNA was positive in 16/95 patients: 3 NOSA-positive and 13 negative. BKV-DNA was negative in 79/95 patients: 22 NOSApositive and 57 negative. The prevalence of NOSA did not differ between BKV-DNA positive and negative patients. It does not seem to exist a relation between BKV and NOSA in renal transplant recipients.

Autoimmunity, a feature of chronic infection by Helicobacter pylori, is first directed against gastric cells but is also associated with extragastric diseases. The aim of the present work was to look for the influence of the infection on induction of non-organ-specific autoantibodies (NOSAs). We compared 49 patients (28 males and 21 females; age range, 36-72 years; mean, 61 +/- 4.6 years) suffering from duodenal ulcer and H. pylori infection (Group A) to 38 subjects (20 male, 18 female; age range, 40-78 years; mean, 63 +/- 3.8 years) affected by duodenal ulcer related to the assumption of nonsteroidal antiinflammatory drugs (Group B). H. pylori infection was diagnosed by histology, 13C-urea breath test, and serum IgG antibodies. Autoimmunitary pattern was demonstrated by the presence of NOSAs in serum. Antinuclear (ANA), anti-smooth muscle (SMA), and anti-liver/kidney microsomal-1 (LKM-1) antibodies were present in 5 of 49 (10.2%), 2 of 49 (4%), and 0 Group A patients, respectively. In Group B, ANA was present in 3 of 38 (7.9%), SMA in 3 of 38 (7.9%), and anti-LKM-1 in 0 patients. The difference was not statistically significant. In this population, H. pylori infection is not associated with an increased prevalence of NOSAs.

Angiotensin II contributes to the post-glomerular arteriolar vasoconstriction which maintains the glomerular filtration rate (GFR) in renal hypoperfusion. To explore whether depressed angiotensin II generation, due to reduced angiotensinogen production or low angiotensin-converting enzyme (ACE) levels, could impair kidney function in advanced cirrhosis.We studied and prospectively followed up 21 diuretic-free ascitic cirrhotic patients, through these determinations: plasma levels of active renin (AR), renin activity (PRA), angiotensin II, ACE and aldosterone; renal clearances of sodium, inulin and para-aminohippurate; antipyrine clearance. Fifteen healthy subjects were also studied.GFR distribution was bimodal, 10 patients had low GFR values (l-GFR group) and 11 had normal-GFR values (n-GFR group) (below and above 105 ml/min per 1.73 m(2) body surface area). Antipyrine clearance and Child-Pugh score did not differ in the two patient groups. l-GFR group had higher AR and PRA values, lower ACE levels and a significantly higher AR/Angiotensin II ratio than n-GFR group (all P0.01). All 21 patients showed increased values of the AR/PRA ratio, i.e. subnormal angiotensinogen levels (P0.03). The 18-month survival rates of l-GFR and n-GFR groups were 20 and 81% (P0.02).Low-GFR cirrhotic patients had a worse survival rate associated with more severe contraction of the effective arterial blood volume, higher AR/Angiotensin II ratio and lower ACE levels.

Interferon alfa (IFN) therapy is efficacious in chronic viral hepatitides. It may, however, cause adverse immunologic reactions in patients with concomitant autoimmune phenomena. A minority of patients with chronic type C hepatitis have antibodies against liver and kidney microsomes (anti-LKM) in serum. We therefore carried out this study to find out whether IFN is safe and efficacious also in this subgroup. We treated 92 consecutive cases of chronic hepatitis C with IFN. Twelve patients had anti-LKMand the remaining 80 tested negative to the anti-LKM. The hepatitis C virus (HCV) infection was diagnosed on the basis of positive anti-HCV and HCV-RNA tests. We compared the clinical and virological virological results of the therapy and the side effects found in the two groups. We found that the response to therapy and the outcome after 1 year of follow-up were similar. Treatment was discontinued in one anti-LKM-positive patient because of a drastic increase in ALT levels at the fourth month of therapy. No untoward effect was observed in the other cases. Hepatitis C patients with anti-LKM may be exposed to an increased risk of an adverse hepatitic reaction while being treated with IFN. However, we found that the extent of the risk was minimal compared with the expected benefits of the therapy. IFN is therefore recommended as the first therapy to choose in these patients. They must, however, be monitored more closely for possible liver dysfunction than the ordinary hepatitis C patient.