[Show abstract][Hide abstract] ABSTRACT: Background:
Patients with inflammatory bowel diseases (IBD) frequently have extraintestinal manifestations including arthritis, sacroiliitis, and ankylosing spondylitis. While the treatment of these rheumatological conditions with traditional non-steroidal anti-inflammatory drugs (NSAIDs) has been reported to lead to frequent IBD exacerbation, the safety of cyclooxygenase-2 (COX-2) inhibitors (Coxibs) remains unclear.
Our aim is to carry out a meta-analysis to verify if Coxibs, employed to treat rheumatological manifestations, are associated with an increased risk of exacerbation of IBD compared to placebo.
Study design and setting:
A MEDLINE, SCOPUS, ISI-Web of Knowledge, and EMBASE search of all studies published in English from 1965 to April 15, 2015, was conducted. Articles on the safety of Coxibs in patients with IBD were identified using the terms "Coxibs or cyclooxygenase-2 inhibitors or COX-2 inhibitors AND inflammatory bowel disease."
The criteria of exclusion of the studies were NSAIDs administration within 2 weeks before starting Coxibs. For the "proportion" meta-analysis, the studies had to report the proportion of patients that had to discontinue the Coxibs therapy due to an exacerbation of IBD; for the "relative risk" meta-analysis, the studies had to be prospective with a comparison between patients taking Coxibs and patients taking placebo. Two authors independently reviewed titles and abstracts of references retrieved from the literature search and selected potentially relevant studies. Differences in opinion were resolved by discussion until consensus was reached. If an agreement failed to be reached, a third author was consulted. The quality of each study was assessed on a 5-point scale adapted from studies by the Quebec Task Force on Whiplash-Associated disorders and Jadad.
The search identified 72 publications of which 7 studies reported the proportion of patients with IBD that had to stop the Coxibs therapy because of a worsening of the activity of IBD. The pooled proportion of flare up of IBD in patients that received Coxibs was 14.4% (95% CI: 6.7 - 24.4%). There was no statistically significant difference between patients that assumed Coxibs and those that assumed placebo (total fixed effect relative risk = 0.86, 95% CI: 0.39 - 1.88, P = 0.7).
A proportion of patients received maintenance therapy with azathioprine or 6-mercaptopurine and these co-interventions could have protected against a Coxib-induced flare; furthermore, the duration of Coxib assumption in the prospective studies is shorter compared to that of the medical practice. Three of the studies included in our meta-analysis had an insufficient quality but due to the higher number of recruited patients, the studies with a better quality had a higher weight in the final result. Moreover, to assess the relative risk of flare up of IBD only randomized controlled trials have been used in the second meta-analysis.
This meta-analysis showed that Coxibs are safe in most patients with IBD. Controlled trials of Coxibs compared with NSAIDs would be useful, at least in patients suffering from rheumatic pain refractory to standard treatment. Key words: Acute pain, ankylosing spondylitis, arthritis, coxibs, chronic pain, inflammatory bowel disease, rheumatic manifestations, sacroiliitis.
[Show abstract][Hide abstract] ABSTRACT: Background & aims:
Surrogate indexes of insulin resistance/sensitivity (IR/IS) are widely used in Non Alcoholic Fatty Liver Disease (NAFLD) although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with NAFLD Fibrosis Score (NFS).
Surrogate indexes were validated by tracer technique (D2-glucose and U-13C-glucose) in the basal state and during an Oral Glucose Tolerance Test (OGTT). The best performing indexes were used in an independent cohort of 145 non-diabetic NAFLD subjects to identify liver damage (fibrosis and NASH).
In the validation NAFLD cohort, HOMA-IR, IGR and ISI Stumvoll had the best association with hepatic IR, while peripheral IS was most significantly related to OGIS, ISI Stumvoll and eMCR(nodem) . In the independent cohort, only OGTT derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (OR=0.76, 95% CI= 0.61-0.96, P=0.0233) and of NASH (OR=0.75, 95% CI=0.63-0.90, P=0.0021). Both OGIS and NFS identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NFS (OR=0.57, 95% CI=0.45-0.72, P<0.001) and was also able to discriminate F2 from F3/F4 (P<0.003).
OGIS is associated with peripheral IS in NAFLD and is inversely associated with an increased risk of significant/advanced liver damage in non-diabetic subjects with NAFLD. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Chronic hepatitis C virus (HCV) infection has been associated with a great number of extra-hepatic manifestations (EHMs), including several endocrine disorders. Currently available epidemiological, clinical and experimental data do not show a link between HCV and all EHMs. Thyroid disorders (TD) and type 2 diabetes, for example, are the most frequent endocrine alterations in patients with chronic HCV infection, but there are only weak evidences that HCV could be involved in hypothalamic-pituitary axis perturbation, bone metabolism alteration and sexual dysfunctions induction. Thus, this issue needs further investigation. Prospective studies have also shown that interferon (IFN)-based therapy for chronic HCV infection can induce or worsen EHMs. In particular, IFN has been associated with development of autoimmunity and/or TD in up to 40% of chronic HCV infected patients. Hence, a careful monitoring of thyroid function should be performed in such patients. The recent approval of direct-acting antiviral agents in IFN-free regimens for chronic hepatitis C treatment will dramatically reduce not only liver-related mortality but also morbidity due to EHMs.
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) develops with high incidence in patients with chronic liver disease (CLD), and particularly in those with cirrhosis. Currently, diagnosis and surveillance are mainly based on imaging-methods. The aim of this study was to evaluate the diagnostic accuracy of highly sensitive measurement of alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-gamma-carboxy-prothrombin (DCP) alone and in combination, for HCC detection. In addition, a recently proposed statistical model, including these three biomarkers plus gender and age, the GALAD model was applied.
In a total of 98 patients [44 CLD patients without HCC (23M, 21F; mean age 53.2±13.4 years) and 54 patients with HCC (45M, 9F; 69.5±9.8 years)] AFP, AFP-L3 and DCP levels were determined using a highly sensitive assay on μTASWako i30 immuno-analyzer. Areas under the curve (AUC), sensitivity (Se) and specificity (Sp) were calculated and compared to assess diagnostic performance of the HCC biomarkers and of the GALAD model.
AFP, AFP-L3 and DCP serum levels were significantly elevated in HCC compared to CLD patients (p<0.0001). AUC values were 0.891, 0.867 and 0.870 respectively. The combination of the 3 biomarkers resulted in AUC=0.947 (Se=94.3%, Sp=86.4%, accuracy=87.6%), whereas the GALAD model showed a AUC=0.976 (Se=96.3, Sp=84.1%, accuracy=89.8%) with a difference between AUC values of 0.029 (p=0.028).
The combination of AFP, AFP-L3 and DCP is superior to a single biomarker in HCC detection. Furthermore, GALAD model performance is significantly higher than simple combination of these 3 biomarkers.
This article is protected by copyright. All rights reserved.
No preview · Article · Jun 2015 · Hepatology Research
[Show abstract][Hide abstract] ABSTRACT: Small intestinal bacterial overgrowth (SIBO) is characterized by an abnormal proliferation of bacterial species in the small bowel. It has been shown that patients with Crohn's disease (CD) have a higher risk of SIBO development. The aim of the present study was to investigate SIBO prevalence in CD patients, possible clinical predictors of SIBO development and response to antibiotic therapy.
Sixty-eight patients (42 male, 26 female; mean age 49.3 ± 12.8 years) with CD reporting abdominal complaints were prospectively evaluated for SIBO with H2/CH4 glucose breath test (GBT).
Of the 68 patients enrolled, 18 (26.5%) tested positive for SIBO. Patients with SIBO exhibited increased stool frequency and significant reduction of stool solidity (p = 0.014), were older than patients tested negative to GBT (54.3 ± 13.0 years vs. 47.5 ± 12.3 years, p = 0.049), reported a longer history of CD (21.2 ± 10.3 years vs. 15.7 ± 10.2 years, p = 0.031) and showed a significant higher frequency of prior surgery (p = 0.001), revealing an association of number of surgical procedures (OR = 2.8315, 95% CI = 1.1525-6.9569, p = 0.023) with SIBO. Breath test normalization occurred in 13/15 patients evaluated after antibiotic and probiotic therapy. Although vitamin B12 levels were lower in patients with SIBO (p = 0.045) and a significant improvement was found after treatment (p = 0.011), this could be due to the heterogeneity, regarding vitamin B12 treatment, in our cohort.
SIBO is a frequent but underestimated condition in CD, which often mimics acute flare, effectively identified with GBT and could be treated with a combined antibiotic and probiotic therapy.
No preview · Article · May 2015 · Scandinavian Journal of Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: Hepatitis B virus (HBV) infection is still a relevant problem worldwide and many cases of hepatocellular carcinoma (HCC) are related to HBV. The prognosis of HBV--related HCC is poor, particularly for advanced stage diagnosis. Although follow--up strategies were adopted for patients at risk, there is need for an optimal early biomarker for the screening purpose. MicroRNAs (miRNAs) are small non--coding RNAs, tightly connected to cell type and differentiation status and act as genetic regulator which can be involved in oncogenic processes. The alteration in miRNA expression pattern may represent a new opportunity for HBV--related HCC diagnosis and therapies. Some studies focused on miRNA polymorphism responsible for HCC susceptibility; others found several miRNAs deregulated by HBV X protein as well as miRNAs altered in HBV--related HCC tissue and cells. A high variability among results emerged, probably due to different techniques employed, biological substrates, experimental procedures, criteria of miRNAs selection and ethnic provenience of the included patients. Interestingly, circulating miRNAs have been studied as potential HCC--biomarkers but the reported accuracy is still not convincing, particularly in distinguishing patients with HCC from patients with cirrhosis. Hence, the use of miRNAs remains in an experimental phase and more studies are required to define their role in the clinical practice.
No preview · Article · Apr 2015 · Panminerva medica
[Show abstract][Hide abstract] ABSTRACT: Currently, there are several drugs approved for the treatment of chronic hepatitis B including recombinant interferons, such as Interferon--α and its pegylated formulation, and the nucleos(t)ide analogues, such as Lamivudine, Adefovir, Telbivudine, Entecavir and Tenofovir. Pegylated--Interferon is an immune--modulatory agent that works mainly by enhancing the innate immune response while nucleos(t)ide analogues are oral drugs with direct inhibition of viral replication. Each agent has its own advantages and drawbacks. Pegylated--Interferon treatment has a finite duration without induction of drug resistance but only a limited number of patients achieve a sustained virological response to therapy. On the other hand, the care with nucleos(t)ide analogues requires a long--term treatment with a potential risk of induction of drug resistance, but higher rates of viral replication suppression are achieved. Nevertheless, second generation nucleos(t)ide analogues, such as Entecavir and Tenofovir, have both high genetic barrier to resistance and potent antiviral action. This review describes the mechanisms of antiviral activity and the efficacy of viral suppression of the different available drugs for chronic hepatitis B treatment, considering the recent clinical guidelines for an optimal management of chronic HBV infection.
No preview · Article · Mar 2015 · Minerva gastroenterologica e dietologica
[Show abstract][Hide abstract] ABSTRACT: Hepatitis B virus (HBV) DNA integration in the host genome is a major mechanism responsible for the etiopathogenetic role exerted by HBV in hepatocellular carcinoma (HCC) development. Extensive analyses evaluating viral integration in HBV surface antigen (HBsAg) negative patients with occult HBV infection (OBI) have not yet been performed. The aim of this study was to investigate and characterize HBV DNA integration in HCC tissues from OBI patients.
Tumour DNA extracts from 69 HCC patients (49 HBsAg-negative with occult infection diagnosed by HBV DNA detection in tumour tissues; 10 HBsAg-positive and 10 HBsAg-negative/OBI-negative as control groups) were examined by Alu-PCR technique to reveal HBV DNA integration into the host genome. The molecular characterization of the virus-genome junctions was performed by cloning and sequencing analyses.
Integrated HBV DNA was detected in 37/49 (75.5%) OBI-positive HCC samples, in 8/10 (80%) HBsAg-positive and in 0/10 OBI-negative HCC samples. Nine of 37 (24.3%) integrated viral sequences from OBI-positive cases were inside human genome coding regions and in the remaining cases the localization at intergenic level was frequently adjacent to coding genes. Concerning viral integrants in OBI cases, X gene sequences were found in 14 cases, preS/S sequences in 13, Core sequences in 7, and Polymerase gene sequences in 3 cases.
In analogy to what occurs in HBsAg-positive cases, HBV DNA integration is highly prevalent in OBI-related HCCs, it mainly involves X and preS/S viral genomic regions and it frequently occurs at the level of regulatory and functional genes. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Full-text · Article · Feb 2015 · Liver international: official journal of the International Association for the Study of the Liver
[Show abstract][Hide abstract] ABSTRACT: SERPINB3 is a cysteine-proteases inhibitor up-regulated in a significant number of cirrhotic patients carrying hepatocellular carcinoma (HCC) and recently proposed as a prognostic marker for HCC early recurrence. SERPINB3 has been reported to stimulate proliferation, inhibit apoptosis and, similar to what reported for hypoxia, to trigger epithelial-to-mesenchymal transition (EMT) and increased invasiveness in liver cancer cells. This study has investigated whether SERPINB3 expression is regulated by hypoxia-related mechanisms in liver cancer cells.
Exposure of HepG2 and Huh7 cells to hypoxia up-regulated SERPINB3 transcription, protein synthesis and release in the extracellular medium. Hypoxia-dependent SERPINB3 up-regulation was selective (no change detected for SERPINB4) and operated through hypoxia inducible factor (HIF)-2α (not HIF-1α) binding to SERPINB3 promoter, as confirmed by chromatin immuno-precipitation assay and silencing experiments employing specific siRNAs. HIF-2α-mediated SERPINB3 up-regulation under hypoxic conditions required intracellular generation of ROS. Immuno-histochemistry (IHC) and transcript analysis, performed in human HCC specimens, revealed co-localization of the two proteins in liver cancer cells and the existence of a positive correlation between HIF-2α and SERPINB3 transcript levels, respectively.
Hypoxia, through HIF-2α-dependent and redox-sensitive mechanisms, up-regulates the transcription, synthesis and release of SERPINB3, a molecule with a high oncogenic potential.
[Show abstract][Hide abstract] ABSTRACT: In 2011 direct-acting antivirals, including telaprevir, have been developed to achieve a better antiviral effect. It was reported that telaprevir is a substrate of P-glycoprotein (ABCB1) and cytochrome P450 3A4. The aim of this retrospective study was the evaluation of the influence of some single nucleotide polymorphisms (SNPs) of genes (ABCB1, SLC28A2/3, SLC29A1) involved in TLV and RBV transport and their correlation with plasma TLV drug exposure at 1 month of therapy. We also investigated the association of a SNP in ABCB11 gene, whose role in TLV transport was not yet shown. Twenty-nine HCV-1 patients treated with telaprevir, ribavirin and pegylated-interferon-α were retrospectively analyzed; allelic discrimination was performed by real-time PCR. Telaprevir Ctrough levels were influenced by Metavir score (P = 0.023), ABCB1 2677 G>T (P = 0.006), ABCB1 1236 C>T (P = 0.015) and ABCB11 1131 T>C (P = 0.033) SNPs. Regarding ABCB1 3435 C>T, a not statistically significant trend in telaprevir plasma concentration was observed. Metavir score (P = 0.002, OR –336; 95% CI –535;–138), ABCB1 2677 (P = 0.020, OR 497; 95% CI 86; 910), ABCB11 1131 (P = 0.002, OR 641; 95% CI 259;1023) and CNT2 -146 (P = 0.006, OR –426; 95% CI –721;–132) were able to predict telaprevir plasma levels in the regression analysis. Other SNPs showed no association. This study reveals BSEP implication in telaprevir transport and confirms the involvement and influence of P-glycoprotein on telaprevir plasma levels. To date, no similar data concerning pharmacogenetics and pharmacokinetics were published, but further studies in different and bigger cohorts are needed.
Full-text · Article · Nov 2014 · Biomedecine [?] Pharmacotherapy