Cardiovascular Compatibility of Proton Pump Inhibitors: Practice Recommendations.

This manuscript aims to critically evaluate the current evidence regarding adverse cardiovascular effects associated with proton pump inhibitors (PPIs) in patients with coronary artery disease (CAD). It also provides guidance for the selection of the most appropriate PPI within the context of cardiovascular polypharmacy and emphasizes the importance of establishing consensus among clinicians on the need to prescribe PPIs with limited cytochrome P450 (CYP450) enzyme inhibition to reduce the risk of drug interactions. PPIs are among the most widely used drugs for the treatment of gastroesophageal reflux disease (GERD) and the prevention of gastrointestinal (GI) bleeding. The manuscript reports the proceedings from the first practice recommendations meeting on the cardiovascular compatibility of PPIs in an Indian setting. A panel of eight Indian experts in cardiology and gastroenterology reviewed 14 consensus statements. Available literature was searched and summarized, and after multiple rounds of review, consensus was achieved for these statements. Based on the available evidence, the consensus panel highlights that a PPI with minimal drug-drug interaction (DDI) is recommended, especially in patients requiring clopidogrel or polypharmacy. Rabeprazole appears to be a good option in cases where co-prescription is indicated, owing to its optimal acid suppression and minimal drug interaction profile.

Epidemiology, Genotyping, Mutational and Phylogenetic Analysis of Hepatitis B Virus Infection in North-east India.

BACKGROUND/OBJECTIVE: Hepatitis B virus (HBV) infection is a major public health problem globally. Northeast India is home to indigenous tribes with different ethnicity and high rates of drug abuse and HIV infection. The study was designed to estimate the burden of HBV infection across various spectrums of liver diseases from this region. HBV genotypes and subgenotypes play a role in the chronicity of disease, response to treatment and its progression. As very limited data are available from this region, we tried to elucidate the role of HBV genotypes, HBV mutants and their phylogenetic analysis. METHOD: We designed a prospective multicentric study, and included 7464 liver disease cases, 7432 blood donors and 650 health care workers, who were screened for HBV infection. HBV DNA positive patients were genotyped and subjected to surface protein, precore and core mutation and phylogenetic analysis. RESULTS: The prevalence of HBV infection with respect to different types of liver diseases, blood donors and health care workers was 9.9% (1550/15,546). 49.5% (768/1550) cases were found to be HBV DNA positive. The most common genotype was found to be genotype D 74.2% (570/768), followed by genotype C 6.5% (50/768), A 4.4% (34/768) and I 0.9% (7/768). CONCLUSION: This study highlights the high hepatitis B burden in Northeast India, reflecting lacunae in health care needs of the region. Also, the different genotype distribution and presence of mutations may translate into different rates of liver disease progression, prognosis and ultimately, clinical significance. However, further prospective cohort study from Northeast India is warranted, to elucidate the clinical significance of multiple genotypes and mutation in this unique population.

IL-10 Polymorphisms and Haplotypes Predict Susceptibility to Hepatocellular Carcinoma Occurrence in Patients with Hepatitis C Virus Infection from Northeast India.

Chronic hepatitis C virus (HCV) infection leads to variable outcomes, ranging from prolonged slow hepatic damage leading to cirrhosis, and hepatocellular carcinoma (HCC). Polymorphism in cytokines IL-10 and IL-12 that impact the immune response to HCV infection may play a role in determining this outcome. This study was aimed to determine if polymorphisms in IL-10 and IL-12B contribute to HCV susceptibility and the risk of developing HCC in patients from Northeast India. IL-10 - 1082, -819, -592 polymorphisms and IL-12B -1188 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism in a total of 266 HCV-infected patients and 100 age- and sex-matched controls. In the HCV-infected subjects, 110 patients had chronic hepatitis C (CHC), 96 with liver cirrhosis, and 60 with HCC. Serum levels of IL-10 were also measured and correlated with disease severity. Haplotype analysis for IL-10 polymorphisms was carried out. Statistical data were analyzed using SPSS ver. 22.0. The frequency of IL-10 - 592 AA genotype/A allele was significantly higher in HCC patients than in CHC patients. The intermediate IL-10-producing ACC haplotype was significantly more frequent in HCC and cirrhotic patients than in CHC patients. No significant association was found for IL-10 - 819, -592 and IL-12B -1188 polymorphisms with the susceptibility to HCV infection or occurrence of HCC in HCV-infected patients. IL-10 - 592 CA polymorphism and IL-10 ACC haplotype are significant biomarkers of HCC in HCV-infected patients from Northeast India. Higher serum levels of IL-10 were also linked to higher disease severity.

Role of VDR, GC, and CYP2R1 Polymorphisms in the Development of Hepatocellular Carcinoma in Hepatitis C Virus-Infected Patients.

Aims: This study was designed to determine if vitamin D receptor (VDR), carrier globulin/binding protein (GC), and cytochrome P-450 family 2, subfamily R, polypeptide 1 (CYP2R1) gene polymorphisms are risk factors in the development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients from Northeast India. Materials and Methods: A total of 351 HCV-infected patients were enrolled of which 167 were diagnosed with chronic hepatitis C (CHC), 124 with liver cirrhosis (LC), and 60 with HCC together with 102 age- and sex-matched healthy controls. VDR (BsmI, ApaI, and TaqI), GC (rs4588, rs7051), and CYP2R1 (rs10741657) gene polymorphisms were genotyped for all subjects. Statistical data were analyzed using SPSS ver. 22.0. Results: The frequency of the ApaI CC genotype, ApaI C allele, and bAt haplotype of the VDR gene was significantly higher in HCC and LC patients than controls. After adjusting for other covariates (age, gender, platelet count, AST, ALT, serum albumin, and viral load) logistic regression analysis showed that the ApaI CC genotype and bAt haplotype were independent predictors of HCC development. No significant associations was found for the GC and CYP2R1 polymorphisms examined with the occurrence of HCC. Conclusions: The presence of the VDR ApaI CC genotype and bAt haplotype appear to be important indicators in the development of HCC among HCV-infected patients. Larger studies are needed to further clarify and establish this potential causal relationship.

INASL Guidelines on Management of Hepatitis B Virus Infection in Patients receiving Chemotherapy, Biologicals, Immunosupressants, or Corticosteroids.

Hepatitis B Virus (HBV) reactivation in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids is emerging to be an important cause of morbidity and mortality in patients with current or prior exposure to HBV infection. These patients suffer a dual onslaught of illness: one from the primary disease for which they are receiving the culprit drug that led to HBV reactivation, and the other from HBV reactivation itself. The HBV reactivation not only leads to a compromised liver function, which may culminate into hepatic failure; it also adversely impacts the treatment outcome of the primary illness. Hence, identification of patients at risk of reactivation before starting these drugs, and starting treatment aimed at prevention of HBV reactivation is the best strategy of managing these patients. There are no Indian guidelines on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids for the treatment of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions, or solid-organ or bone marrow transplantation. The Indian National Association for Study of the Liver (INASL) had set up a taskforce on HBV in 2016, with a mandate to develop consensus guidelines for management of various aspects of HBV infection, relevant to India. In 2017 the taskforce had published the first INASL guidelines on management of HBV infection in India. In the present guidelines, which are in continuation with the previous guidelines, the issues on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids are addressed.

INASL Position Statements on Prevention, Diagnosis and Management of Hepatitis B Virus Infection in India: The Andaman Statements.

Hepatitis B Virus (HBV) infection is one of the major causes of morbidity, mortality and healthcare expenditure in India. There are no Indian consensus guidelines on prevention, diagnosis and management of HBV infection. The Indian National Association for Study of the Liver (INASL) set up a taskforce on HBV in 2016, with a mandate to develop consensus guidelines for diagnosis and management of HBV infection, relevant to disease patterns and clinical practices in India. The taskforce first identified contentious issues on various aspects of HBV management, which were allotted to individual members of the taskforce who reviewed them in detail. A 2-day round table discussion was held on 11th and 12th February 2017 at Port Blair, Andaman & Nicobar Islands, to discuss, debate, and finalize the consensus statements. The members of the taskforce reviewed and discussed the existing literature threadbare at this meeting and formulated the 'INASL position statements' on each of the issues. The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system with minor modifications. The strength of recommendations (strong: 1, weak: 2) thus reflects the quality (grade) of underlying evidence (A, B, C, D). We present here the INASL position statements on prevention, diagnosis and management of HBV in India.

Alteration in the expression of MGMT and RUNX3 due to non-CpG promoter methylation and their correlation with different risk factors in esophageal cancer patients.

Promoter methylation reflects in the inactivation of different genes like O6-methylguanine-DNA methyltransferase DNA repair gene and runt-related transcription factor 3, a known tumor suppressor gene in various cancers such as esophageal cancer. The promoter methylation was evaluated for O6-methylguanine-DNA methyltransferase and runt-related transcription factor 3 in CpG, CHH, and CHG context (where H is A, T, or C) by next-generation sequencing. The methylation status was correlated with quantitative messenger RNA expression. In addition, messenger RNA expression was correlated with different risk factors like tobacco, alcohol, betel nut consumption, and smoking habit. CpG methylation of O6-methylguanine-DNA methyltransferase promoter had a positive association in the development of esophageal cancer (p < 0.05), whereas runt-related transcription factor 3 promoter methylation showed no significant association (p = 1.0) to develop esophageal cancer. However, the non-CpG methylation, CHH, and CHG were significantly correlated with O6-methylguanine-DNA methyltransferase (p < 0.05) and runt-related transcription factor 3 (p < 0.05) promoters in the development of esophageal cancer. The number of cytosine converted to thymine (C→T) in O6-methylguanine-DNA methyltransferase promoter showed a significant correlation between cases and controls (p < 0.05), but in runt-related transcription factor 3 no such significant correlation was observed. Besides, messenger RNA expression was found to be significantly correlated with promoter hypermethylation of O6-methylguanine-DNA methyltransferase and runt-related transcription factor 3 in the context of CHG and CHH (p < 0.05). The CpG hypermethylation in O6-methylguanine-DNA methyltransferase showed positive (p < 0.05) association, whereas in runt-related transcription factor 3, it showed contrasting negative association (p = 0.23) with their messenger RNA expression. Tobacco, betel nut consumption, and smoking habits were associated with altered messenger RNA expression of O6-methylguanine-DNA methyltransferase (p < 0.05) and betel nut consumption and smoking habits were associated with runt-related transcription factor 3 (p < 0.05). There was no significant association between messenger RNA expression of O6-methylguanine-DNA methyltransferase and runt-related transcription factor 3 with alcohol consumption (p = 0.32 and p = 0.15). In conclusion, our results suggest that an aberrant messenger RNA expression may be the outcome of CpG, CHG, and CHH methylation in O6-methylguanine-DNA methyltransferase, whereas outcome of CHG and CHH methylation in runt-related transcription factor 3 promoters along with risk factors such as consumption of tobacco, betel nut, and smoking habits in esophageal cancer from Northeast India.

Polymorphisms in Heat Shock Proteins A1B and A1L (HOM) as Risk Factors for Oesophageal Carcinoma in Northeast India.

BACKGROUND: To investigate polymorphisms in heat shock proteins A1B and A1L (HOM) and associated risk of oesophageal carcinoma in Northeast India. MATERIALS AND METHODS: The study includes oesophageal cancer (ECA) patients attending general outpatient department (OPD) and endoscopic unit of Gauhati Medical College. Patients were diagnosed based on endoscopic and histopathological findings. Genomic DNA was typed for HSPA1B1267 and HSPA1L2437 SNPs using the polymerase chain reaction with restriction fragment length polymorphisms. RESULTS: A total of 78 cases and 100 age-sex matched healthy controls were included in the study with a male: female ratio of 5:3 and a mean age of 61.4±8.5 years. Clinico-pathological evaluation showed 84% had squamous cell carcinoma and 16% were adenocarcinoma. Dysphagia grades 4 (43.5%) and 5 (37.1%) were observed by endoscopic and hispathological evaluation. The frequency of genomic variation of A1B from wild type A/A to heterozygous A/G and mutant G/G showed a positive association [chi sq=19.9, p= <0.05] and the allelic frequency also showed a significant correlation [chi sq=10.3, with cases vs. controls, OR=0.32, p≤0.05]. The genomic variation of A1L from wild T/T to heterozygous T/C and mutant C/C were found positively associated [chi sq= 7.02, p<0.05] with development of ECA. While analyzing the allelic frequency, there was no significant association [chi sq= 3.19, OR=0.49, p=0.07]. Among all the risk factors, betel quid [OR =9.79, Chi square= 35.0, p<0.05], tobacco [OR = 2.95, chi square=10.6, p<0.05], smoking [OR=3.23, chi square=10.1, p<0.05] demonstrated significant differences between consumers vs. non consumers regarding EC development. Alcohol did not show any significant association [OR= 1.34, chi square=0.69, p=0.4] independently. CONCLUSIONS: It can be concluded that the present study provides marked evidence that polymorphisms of HSP70 A1B and HSP70 A1L genes are associated with the development of ECA in a population in Northeast India, A1B having a stronger influence. Betel quid consumption was found to be a highly significant risk factor, followed by smoking and tobacco chewing. Although alcohol was not a potent risk factor independently, alcohol consumption along with tobacco, smoking and betel nut was found to contribute to development of ECA.