Genetic and Immune Predictors for Hypersensitivity Syndrome to Antiepileptic Drugs

Hypersensitivity syndrome reactions (HSR) to antiepileptic drugs (AED) are associated with severe clinical cutaneous adverse reactions (SCAR).Our aims are: to assess HSRs to AEDs using the in vitro lymphocyte toxicity assay (LTA) in patients who manifested HSRs clinically, to correlate LTA results with the clinical syndrome, to correlate LTA results with the human leukocyte antigen (HLA) allele B*1502 (HLA-B*1502) positivity in a Han Chinese-Canadian population, and to determine the cytokine network in this population. HSR patients developed fever and cutaneous eruptions in the presence or absence of organ involvement within 8 weeks of exposure to carbamazepine (CBZ), phenytoin (PHY) or lamotrigine (LTG). Control patients received AEDs without presenting HSR. We investigated 10 CBZ-HSR (4 presented with Stevens-Johnson syndrome (SJS)), 24 CBZ-controls, 10 PHY-HSR (4 presented with drug-induced liver injury (DILI)), 24 PHY-controls, 6 LTG-HSR (1 SJS and 1 DILI) and 24 LTG-controls. There were 30 Han Chinese individuals (14 HSR patients and 16 controls) in our cohort. LTA toxicity greater than 12.5%±2.5% was considered positive. Differences among groups were determined by analysis of variance. In addition, we measured cytokine secretion in the patient sera between 1 month and 3 years after the event. All Han Chinese individuals and 30% of Caucasians were genotyped for HLA-B*1502.A perfect correlation (r=0.92) was observed between positive LTA and clinical diagnosis of DILI and SJS/toxic epidermal necrolysis (TEN). HLA-B*1502 positivity in Han Chinese is a predictor of CBZ-HSR and PHY-HSR. HLA-B*1502-negative Han Chinese receiving only CBZ or a combination of CBZ-PHY tolerated the drug(s) clinically, presenting negative CBZ-LTA and PHY-LTA. However, 3 patients presenting negative CBZ-LTA and PHY-LTA, as well as negative HLA-B*1502, showed positive LTG-LTA (38%, 28% and 25%, respectively), implying that they should not be prescribed LTG. Three patients had LTA positive to both PHY and CBZ, and 3 others had LTA positive to both PHY and LTG. Clinically, all six patients presented HSR to both drugs that they tested positive to (cross-reactivity). Patients were grouped based on the clinical presentation of their symptoms as only rash and fever or a triad that characterizes "true" HSR (rash, fever and DILI or SJS/TEN). Levels of pro-inflammatory cytokines were significantly higher in patient sera compared to control sera. More specifically, the highest levels of tumor necrosis factor (TNF)-α was measured in patients presenting "true" HSR, as were the apoptotic markers Fas, caspase 8 activity and M30. We concluded that LTA is sensitive for DILI and SJS/TEN regardless of drug or ethnicity. HSR prediction will prevent AED-induced morbidity. In Han Chinese, HLA-B*1502 positivity is a predictor for CBZ-HSR and PHY-HSR. Its negativity does not predict a negative LTG-HSR. There is cross-reactivity between AEDs. Additionally, T-cell cytokines and chemokines control the pathogenesis of SJS/TEN and DILI, contributing to apoptotic processes in the liver and in the skin

The Link between Hypersensitivity Syndrome Reaction Development and Human Herpes Virus-6 Reactivation

Background. There are challenges in the clinical diagnosis of drug-induced injury and in obtaining information on the reactivation of human herpes viruses (HHV) during idiosyncratic adverse drug reactions. Objectives. (i) To develop a unified list of drugs incriminated in drug-induced hepatotoxicity and severe cutaneous reactions, in which drug hypersensitivity leads to HHV-6 reactivation and further complication of therapy and recovery and (ii) to supplement the already available data on reporting frequencies of liver- or skin-induced cases with knowledge of individual case reports, including HHV-6 reactivation and briefly introducing chromosomally integrated HHV-6. Data Sources and Extraction. Drugs identified as causes of (i) idiosyncratic reactions, (ii) drug-induced hypersensitivity, drug-induced hepatotoxicity, acute liver failure, and Stevens-Johnson syndrome, and (iii) human herpes virus reactivation in PubMed since 1997 have been collected and discussed. Results. Data presented in this paper show that HHV-6 reactivation is associated with more severe organ involvement and a prolonged course of disease. Conclusion. This analysis of HHV-6 reactivation associated with drug-induced severe cutaneous reactions and hepatotoxicity will aid in causality assessment and clinical diagnosis of possible life-threatening events and will provide a basis for further patient characterization and therapy

HIV-Antiretroviral Therapy Induced Liver, Gastrointestinal, and Pancreatic Injury

The present paper describes possible connections between antiretroviral therapies (ARTs) used to treat human immunodeficiency virus (HIV) infection and adverse drug reactions (ADRs) encountered predominantly in the liver, including hypersensitivity syndrome reactions, as well as throughout the gastrointestinal system, including the pancreas. Highly active antiretroviral therapy (HAART) has a positive influence on the quality of life and longevity in HIV patients, substantially reducing morbidity and mortality in this population. However, HAART produces a spectrum of ADRs. Alcohol consumption can interact with HAART as well as other pharmaceutical agents used for the prevention of opportunistic infections such as pneumonia and tuberculosis. Other coinfections that occur in HIV, such as hepatitis viruses B or C, cytomegalovirus, or herpes simplex virus, further complicate the etiology of HAART-induced ADRs. The aspect of liver pathology including liver structure and function has received little attention and deserves further evaluation. The materials used provide a data-supported approach. They are based on systematic review and analysis of recently published world literature (MedLine search) and the experience of the authors in the specified topic. We conclude that therapeutic and drug monitoring of ART, using laboratory identification of phenotypic susceptibilities, drug interactions with other medications, drug interactions with herbal medicines, and alcohol intake might enable a safer use of this medication

Alcoholic and non-alcoholic steatohepatitis

This paper is based upon the “Charles Lieber Satellite Symposia” organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its comorbidities with chronic viral hepatitis in the presence or absence of human deficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism

Biomolecules and Biomarkers Used in Diagnosis of Alcohol Drinking and in Monitoring Therapeutic Interventions

Background: The quantitative, measurable detection of drinking is important for the successful treatment of alcohol misuse in transplantation of patients with alcohol disorders, people living with human immunodeficiency virus that need to adhere to medication, and special occupational hazard offenders, many of whom continually deny drinking. Their initial misconduct usually leads to medical problems associated with drinking, impulsive social behavior, and drunk driving. The accurate identification of alcohol consumption via biochemical tests contributes significantly to the monitoring of drinking behavior. Methods: A systematic review of the current methods used to measure biomarkers of alcohol consumption was conducted using PubMed and Google Scholar databases (2010–2015). The names of the tests have been identified. The methods and publications that correlate between the social instruments and the biochemical tests were further investigated. There is a clear need for assays standardization to ensure the use of these biochemical tests as routine biomarkers. Findings: Alcohol ingestion can be measured using a breath test. Because alcohol is rapidly eliminated from the circulation, the time for detection by this analysis is in the range of hours. Alcohol consumption can alternatively be detected by direct measurement of ethanol concentration in blood or urine. Several markers have been proposed to extend the interval and sensitivities of detection, including ethyl glucuronide and ethyl sulfate in urine, phosphatidylethanol in blood, and ethyl glucuronide and fatty acid ethyl esters in hair, among others. Moreover, there is a need to correlate the indirect biomarker carbohydrate deficient transferrin, which reflects longer lasting consumption of higher amounts of alcohol, with serum γ-glutamyl transpeptidase, another long term indirect biomarker that is routinely used and standardized in laboratory medicine

Biomolecules and Biomarkers Used in Diagnosis of Alcohol Drinking and in Monitoring Therapeutic Interventions

Background: The quantitative, measurable detection of drinking is important for the successful treatment of alcohol misuse in transplantation of patients with alcohol disorders, people living with human immunodeficiency virus that need to adhere to medication, and special occupational hazard offenders, many of whom continually deny drinking. Their initial misconduct usually leads to medical problems associated with drinking, impulsive social behavior, and drunk driving. The accurate identification of alcohol consumption via biochemical tests contributes significantly to the monitoring of drinking behavior. Methods: A systematic review of the current methods used to measure biomarkers of alcohol consumption was conducted using PubMed and Google Scholar databases (2010–2015). The names of the tests have been identified. The methods and publications that correlate between the social instruments and the biochemical tests were further investigated. There is a clear need for assays standardization to ensure the use of these biochemical tests as routine biomarkers. Findings: Alcohol ingestion can be measured using a breath test. Because alcohol is rapidly eliminated from the circulation, the time for detection by this analysis is in the range of hours. Alcohol consumption can alternatively be detected by direct measurement of ethanol concentration in blood or urine. Several markers have been proposed to extend the interval and sensitivities of detection, including ethyl glucuronide and ethyl sulfate in urine, phosphatidylethanol in blood, and ethyl glucuronide and fatty acid ethyl esters in hair, among others. Moreover, there is a need to correlate the indirect biomarker carbohydrate deficient transferrin, which reflects longer lasting consumption of higher amounts of alcohol, with serum γ-glutamyl transpeptidase, another long term indirect biomarker that is routinely used and standardized in laboratory medicine

Safety of Anti-Tumor Necrosis Factor Therapies in Arthritis Patients

Purpose. Inflammatory and rheumatic arthritis remain leading causes of disability worldwide. The arthritis therapeutic area commands the largest market for the prescription of biological and non-steroidal anti-inflammatory drugs (NSAID). Yet biotechnology and pharmaceutical companies conducting research and providing therapeutics in this area frequently face challenges in patient safety.  The purpose of our study was to assess safety of anti-tumor necrosis factor therapies in arthritis patients.  Methods: The present study systematically reviews adverse events of biologicals alone or in the presence of NSAIDs and other immunosuppressant therapeutics such as disease-modifying antirheumatic drugs (DMARD). We assessed the rheumatology literature that included clinical trials with anti-tumor necrosis factor (TNF) biologicals and case reports published between 2010 and 2014.  Results: Currently approved anti-TNF biologicals in arthritis include the monoclonal antibodies infliximab, adalimumab, certolizumab pegol and golimumab, and the fusion protein etanercept. The most frequently-reported adverse event was infection. We grouped the adverse reactions as immune-mediated, hypersensitivity syndrome reactions including cutaneous and hepatic manifestation, neurological, hematological, and malignancy.  Discussion: Most adverse events are due to the failure of host immunological control, which involves susceptibility to the drug itself, or de novo infection or reactivation of a latent bacterial or viral infection, often with a different expression of disease. Drug-induced liver injury associated with anti-TNF biologicals must be kept in mind when evaluating patients with increased liver enzymes.  Conclusion: Risk assessment in individuals undergoing treatment with biologicals represents a step towards achieving a personalized medicine approach to identify those patients that will safely benefit from this therapeutic approach. Patients and physicians must be alert of anti-TNF agents as potential causes of drug-induced liver injury and monitor the therapies. Personalizing therapeutic pharmacovigilance promises to optimize benefits while minimizing side effects. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page

Biomarkers in Nonalcoholic Fatty Liver Disease

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition characterized by insulin resistance, type 2 diabetes and fat accumulation in the liver that may cause hepatic inflammation and progressive scarring leading to nonalcoholic steatohepatitis (NASH) and irreversible liver damage (cirrhosis). As a result, there has been increased recognition of the need to assess and closely monitor individuals for risk factors of components of NAFLD and NASH, as well as the severity of these conditions using biomarkers