Association of Cytokines with Clinical Indicators in Patients with Drug-Induced Liver Injury

Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury(DILI)caused by different drugs and their correlation with clinical indicators.Method The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests(RUCAM)scoring criteria and clinically diagnosed with DILI.Based on Chinese herbal medicine,cardiovascular drugs,non-steroidal anti-inflammatory drugs(NSAIDs),antiinfective drugs,and other drugs,patients were divided into five groups.Cytokines were measured by Luminex technology.Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed.Results 73 patients were enrolled.Age among five groups was statistically different(P=0.032).Alanine aminotransferase(ALT)(P=0.033)and aspartate aminotransferase(AST)(P=0.007)in NSAIDs group were higher than those in chinese herbal medicine group.Interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α)in patients with Chinese herbal medicine(IL-6:P<0.001;TNF-α:P<0.001)and cardiovascular medicine(IL-6:P=0.020;TNF-α:P=0.001)were lower than those in NSAIDs group.There was a positive correlation between ALT(r=0.697,P=0.025),AST(r=0.721,P=0.019),and IL-6 in NSAIDs group.Conclusion Older age may be more prone to DILI.Patients with NSAIDs have more severe liver damage in early stages of DILI,TNF-αand IL-6 may partake the inflammatory process of DILI.

Recent developments in immunotherapy approaches for allergic rhinitis

Allergic rhinitis(AR)poses a significant global health burden,with the potential to progress to asthma,thereby impacting patients’quality of life.Immunotherapy has demonstrated effectiveness in mitigating clinical symptoms by altering the underlying disease mechanisms of AR.This article provides a thorough review of the current state of immunotherapy for AR,encompassing various facets of immunotherapeutic strategies,elucidating their mechanisms and clinical implications.By presenting a nuanced understanding of the present landscape of immunotherapy for AR,this review aims to serve as a valuable reference for informing clinical treatment strategies.The subsequent analysis of diverse immunotherapeutic pathways offers a comprehensive understanding of their mechanisms and clinical implications.A meticulous examination is conducted on subcutaneous immunotherapy,sublingual immunotherapy,oral immunotherapy,intralymphatic immunotherapy,and innovative intravenous gold-induced autologous serum injection therapy.Each pathway is systematically elucidated,with its distinctive features and potential contributions to managing AR emphasized.In conclusion,synthesizing epidemiological insights,immunotherapeutic nuances,and pathway-specific analyses encapsulates a profound understanding of immunotherapy for AR.

Progress in the Application of Mendelian Randomization Analysis in Allergic Rhinitis

Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease of the nasal mucosa mediated mainly by immunoglobulin E (IgE) in atopic individuals after exposure to allergens, with the typical symptoms of paroxysmal sneezing, watery runny nose, itchy nose and nasal congestion. Mendelian randomization (MR), an innovative epidemiological approach that uses common genetic variants as instrumental variables for exposure, thus enabling prediction of their causal relationship with outcomes, has been widely used in recent years in studies related to AR. This paper provides a review of the method and its progress in the field of allergic rhinitis research.

Effects of Yigan Capsule on the expression of HMGB1,RAGE and NF-κB protein in rats with drug-induced liver injury

Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced liver injury(ATB-DILI),and to explore its protective effect and mechanism on ATB-DILI,so as to provide experimental basis for the clinical application of Yigan capsule.Methods:Twenty-four rats were divided into two groups.Except for the blank group(n=6),the other 18 rats were given isoniazid(INH)+rifampicin(RFP)(50 mg/kg.d)for 4 weeks.Then 18 rats were randomly divided into three groups(model group,low dose group of Yigan capsule and high dose group of Yigan capsule)according to 6 rats in each group.The blank group and the model group were given 0.9%sodium chloride solution by intragastric administration.The low dose group of Yigan capsule was 0.468 g/kg,and the high dose group of Yigan capsule was 1.872 g/kg[1].After 4 weeks,the pathological changes of liver were observed by HE staining.The contents of ALT,AST,ALP,γ-GT and TBIL were detected.The expression of HMGB1,NF-κBp65 and RAGE protein was detected by IHC.The expression levels of HMGB1,NF-κBp65,RAGE,TNF-αand IL-1βwere detected by WB.Result:HE staining showed that the structure of the liver in the model group was disordered,the liver cells showed swelling and fusion,the number of inflammatory cells increased and accompanied by punctate necrosis,while the above pathological changes in each treatment group of Yigan capsule were significantly improved.The contents of ALT,AST,ALP,γ-GT and TBIL in the model group were higher than those in the blank group(P<0.05).The contents of ALT,AST,ALP,γ-GT and TBIL in each treatment group were significantly lower than those in the model group(P<0.05).Compared with the blank group,the expression levels of TNF-αand IL-1βin the model group were increased(P<0.05),and the expression levels of HMGB1,NF-κBp65 and RAGE were increased(P<0.05).Compared with the model group,the expression levels of TNF-αand IL-1βin each treatment group of Yigan capsule decreased(P<0.05),and the expression of HMGB1,NF-κBp65 and RAGE decreased(P<0.05).Conclusion:Yigan capsule may inhibit the secretion of inflammatory factors through HMGB1/RAGE/NF-κBp65 signaling pathway,thus protecting ATB-DILI.

Establishment and Evaluation of a Mouse Model of Allergic Rhinitis

[Objectives]To explore a new method for induction of allergic rhinitis in mice,and compare and evaluate it with common modeling methods.[Methods]36 mice were randomly divided into the control group,blank group and experimental group,and there were 12 mice in each group.The mice in the control group were conventionally induced.That is,the mice were first injected intraperitoneally with the mixture composed of OVA 50μg,[Al(OH)3]5 mg and 1ml of normal saline once every other day,and then since the 15 th d,20μL of 5%OVA solution was dropped into each nasal cavity once a day,which lasted for 7 d.The blank group was treated with the same amount of normal saline according to the control group,and received intraperitoneal injection and bilateral nasal drip respectively.In the experimental group,mice were first given intraperitoneal injection of the mixture composed of ovalbumin(OVA)75μg,aluminum hydroxide gel[Al(OH)3]8 mg and normal saline 1.5 mL for basic sensitization.On the 26 th d,20μL of 3%OVA solution was dropped into each nasal cavity once a day,which lasted for 10 d.The number of sneezes,the number of nose scratching,the amount of nasal discharge,and the activity of mice in each group were observed,and the behavior of allergic reaction was scored.Meanwhile,the number of eosinophils in the nasal discharge of mice and the IgE content in serum were measured.[Results]The score of nasal stimulation symptoms,the number of eosinophils and serum IgE level of mice in the control group and the experimental group were higher than those in the blank group(P<0.05),and there was no statistical significance between the two groups in the three indicators(P>0.05).[Conclusions]The modeling method was more suitable for the development of allergic rhinitis patients condition,and reduced the probability of death of mice due to modeling,and simplified the experimental operation.

Overview of Research on the Clinical Treatment of Allergic Rhinitis

Three kinds of treatment for allergic rhinitis(Western medicine,traditional Chinese medicine and their combination)were described respectively,and the different treatment methods of AR and their characteristics were analyzed.This study will help to further improve the diagnosis and treatment of the disease and promote the early recovery of patients.

Effect of Centipeda Herba Volatile Oil on Allergic Rhinitis by Nasal Sniffing

[Objectives] To explore the efficacy of different concentrations of Centipeda Herba volatile oil in the treatment of allergic rhinitis (AR) by nasal sniffing and the optimal drug concentration.[Methods] Forty-eight mice were randomly divided into control group, blank group, alcohol treatment group, low concentration group, medium concentration group and high concentration group, with 8 mice in each group. Except for the blank group, each mouse in the other groups was intraperitoneally injected with 1 mL of a mixture of 50 μgOVA+5 mg [Al(OH) 3] +1 mL of normal saline for 14 d. The allergic rhinitis mouse model was successfully established by intranasal instillation of 5% OVA solution on both sides (20 μL per side, once a day) from the 15 th day after stimulation for 7 d. The blank group was treated with the same amount of saline as above. The volatile oil of Centipeda Herba was obtained by steam distillation and petroleum ether extraction, and then was made into 1.25%, 2.5% and 5% volatile oil of Centipeda Herba with 75% alcohol. The control group was stimulated once every other day with reagent 2 after 7 d of stimulation (maintenance) until the end of treatment. The blank group was treated with 5 mL saline by nasal sniffing for 30 d, twice in the morning and evening, 30 min each time. The alcohol treatment group was treated with 5 mL of 75% alcohol, and the low concentration group, the medium concentration group and the high concentration group were treated with 5 mL of 1.25%, 2.5% and 5% Centipeda Herba volatile oil, respectively. The treatment time was the same as that of the blank group, and the treatment process was carried out in their respective closed contamination boxes. Before and after the treatment, the frequency of sneezing, the frequency of scratching nose, the amount of nasal discharge, activity and other general characteristics of the mice were observed, and the allergic behavior score was carried out. Besides, the IgE content in the serum of the mice was determined, and the eosinophils in the nasal discharge were counted.[Results] The scores of mice before and after treatment showed that there was no significant difference in the alcohol treatment group before and after treatment ( P >0.05), and there was significant difference in the low, medium and high concentration groups before and after treatment ( P <0.05), except that there was no significant difference between the control group and the alcohol treatment group ( P >0.05), and there was significant difference among the other groups ( P <0.05). The levels of IgE and the number of eosinophils in peripheral serum of mice in the control group, alcohol treatment group, low concentration group, medium concentration group and high concentration group were higher than those in the blank group ( P <0.05), and there was no significant difference between the two groups ( P >0.05).[Conclusions] Volatile oil of Centipeda Herba can be used to treat allergic rhinitis by nasal sniffing, and 5% volatile oil of Centipeda Herba has the best effect. During the treatment, sneezing and runny nose in mice were reduced. The results showed that nasal sniffing was less irritating to the nasal cavity and not easy to produce discomfort, the utilization rate of drugs was higher than that of traditional therapy, and the volatile oil could be preserved longer than that of traditional Chinese medicine.

Different medications for seasonal allergic rhinitis in adults:A systematic review and meta-analysis

BACKGROUND While the efficacy of medications such as fluticasone furoate(FF),fluticasone propionate(FP),and azelastine-fluticasone(AF)has been substantiated in comparison to their respective placebo controls,uncertainties persist regarding the comparative effectiveness of different intranasal agents.AIM To evaluate the efficacy of FP,FF,and AF in the treatment of adult patients with seasonal allergic rhinitis(SAR)using a meta-analytic approach.METHODS A computer search was conducted in Cochrane Library,PubMed,and EMBASE databases to identify randomized controlled trials assessing the effectiveness and safety of FF,FP,and AF in treating SAR.Data on treatment safety and efficacy were extracted and analyzed through meta-analysis.RESULTS A total of 20 studies were included,comprising 10590 participants.The results of the direct meta-analysis indicated that,compared to placebo,both relative Total Nasal Symptom Score(rTNSS)and relative Total Ocular Symptom Score(rTOSS)significantly decreased post-intervention[mean difference(MD)=-1.48,95%confidence interval(CI):-1.73 to-1.22;MD=-0.66,95%CI:-0.82 to-0.49],with similar findings observed across the FF,FP,and AF subgroups.The network meta-analysis results showed that for improving rTNSS and rTOSS,the SUCRA values ranking from highest to lowest were AF,FP,FF,and placebo.Improvements in rTNSS and rTOSS with FP,FF,and AF were all significantly greater than those observed with placebo,with AF demonstrating superior efficacy compared to both FP and FF.No statistically significant difference in rTNSS improvement was found between FP and FF,although FP exhibited significantly greater improvement in rTOSS compared to FF.CONCLUSION In adult patients with SAR,the combination of azelastine and fluticasone shows a significant effect in improving nasal and ocular symptoms,with FP demonstrating marked improvement in ocular symptoms compared to FF.

Epidemiological Features of Allergic Rhinitis in Four Major Cities in Western China

Allergic rhinitis（AR）,with an increasing uptrend of the prevalence in many developed and developing countries,is a global health problem that affects people of all ages and ethnic groups.However,data on the prevalence of self-reported AR in western China are rare.This study investigated the epidemiological features of self-reported AR in western China.In the cross-sectional,population-based study,a validated questionnaire survey on self-reported AR was carried out in 4 major cities in western China by multistage,stratified and cluster sampling,from January to December 2008.The total prevalence rate was 34.3%,with 32.3%（Chongqing）,34.3%（Chengdu）,37.9%（Urumqi）,30.3%（Nanning）,respectively.The prevalence presented to increase with age before 30 years old while decrease with age after 30 years old,and the highest prevalence was in 19-30 years group in Chongqing,Chengdu and Nanning which significantly showed ＂persistent and moderate-severe＂ type（P0.0001）;In Urumqi,there wasn＇t a significant increasing or decreasing trend of prevalence rate with age but with an ＂intermittent and mild＂predominance（P0.0001）.There were no distinct sexual differences in prevalence rates in the 4 cities.The morbidity was positively related to monthly average temperature and sunshine（r=0.76645,P=0.0036;r=0.67303,P=0.0165）,but negatively associated with relative humidity（r=-0.64391,P=0.0238） in Urumqi.Interestingly,the monthly morbidity was negatively associate with average temperature,sunshine and precipitation in Nanning（r=-0.81997,P=0.0011;r=-0.60787,P=0.0360;r=-0.59443,P=0.0415）.Self-reported AR is becoming common in western China with a rapid development in recent years,affecting about three persons out of ten.The climatic factors may have an indirect impact on the prevalence rate through the effects on the local allergens.

Drug-induced autoimmune hepatitis:A minireview

Drug-induced autoimmune hepatitis(DIAIH)is a specific phenotype of druginduced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation.Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline,non-steroidal anti-inflammatory drugs,statins as well as anti-tumor necrosis agents.The clinical features of druginduced liver injury are indistinguishable from idiopathic autoimmune hepatitis(AIH)as both may have positive AIH-related autoantibodies,elevated immunoglobulin G,as well as similar histopathological findings.In patients who show no clinical improvement,or there is progressive liver injury despite cessation of the suspected drug,a liver biopsy should be considered,whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH.Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury.A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper.In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature.Early identification and treatment often lead to a favorable outcome in DIAIH.

CD4+Foxp3+CD25+/-Tregs characterize liver tissue specimens of patients suffering from drug-induced autoimmune hepatitis:A clinical-pathological study

Background: The diagnosis of drug-induced autoimmune hepatitis(DIAIH) and its differentiation from idiopathic autoimmune hepatitis(AIH) is challenging. This study aimed to differentiate DIAIH from AIH by comparing the biochemical changes, histological features, and frequencies of CD4~+Foxp3~+CD25+/-regulatory T cells(Tregs) in liver tissues or peripheral blood lymphocytes.Methods: A total of 15 DIAIH patients and 24 AIH patients who underwent liver biopsies at initial presentation were enrolled in this study. The liver histological changes were assessed by HE staining. The phenotypic recognition and distribution of CD4~+Foxp3~+CD25+/-Tregs in liver tissues were evaluated by single/double immunostains in serial sections. The CD4~+Foxp3~+CD25+/-Tregs in peripheral blood were analyzed by flow cytometry.Results: The median values of ALT and AST were 404.50 U/L and 454.10 U/L in DIAIH patients and309.50 U/L and 315.00 U/L in AIH patients, respectively. More importantly, for the first time we found that patients with DIAIH had higher levels of serum ALT and AST, more severe degree of lobular inflammation,higher frequencies of zone 3 necrosis and higher number of lobular CD4~+Foxp3~+CD25~-Tregs compared with AIH(P < 0.05). Furthermore, there were positive correlations in DIAIH between the degree of lobular inflammation and either the AST/ALT level or the number of lobular CD4~+Foxp3~+CD25~-Tregs(P < 0.05).However, the frequency of peripheral blood CD4~+Foxp3~+CD25+/-Tregs were not significantly different between DIAIH and AIH.Conclusions: The differences of ALT, AST and the number of lobular CD4~+Foxp3~+CD25~-Tregs between patients with DIAIH and those with AIH are clinically helpful in differentiating these two diseases in their early stage.

Overview on drug-induced liver injury in Brazil

Drug-induced liver injury(DILI)is an uncommon event in clinical practice,which makes knowing its true incidence difficult.Prospective,retrospective and registry-based studies are the most important methods to obtain epidemiological data on DILI.Latin America(LA)has a historical lack of prospective studies on this topic.New definitions and the creation of hepatotoxicity registries have significantly improved the epidemiological understanding of hepatic drug reactions in several regions of the world.The Latin American DILI network,referred to as LATINDILI,has been created in 2011,and recently published its own DILI recommendations describing the most relevant issues on the management of hepatotoxicity in general,and those based on findings from our own LA experience in particular.Although most of the registries do not carry out population-based studies,they may provide important data related to the prevalence of DILI.The joint work among researchers and the corresponding health and regulatory authorities should be stimulated due to the high impact that hepatotoxicity represents for public health.

Effect of RNA interference therapy on the mice eosinophils CCR3 gene and granule protein in the murine model of allergic rhinitis

Objective:To observe the clinical manifestations of allergic rhinitis mice and the expression changes of the eosinophils CCR3 and the granule protein rnRNA in the bone marrow,peripheral blood and nasal lavage fluid.Mctliods:Twenty-four BALB/c mice were randomly divided into the control group.PBS therapy group.siKNA therapy group and the CCR3 siRNA therapy group(n=6).Allergic rhinitis model were sensitized and stimulated by ovalbunfin,and CCR3 siKNA therapy group were administered with CCH3 transnasally before stimulated.The levels of the eosinophils CCR3.MBP.ECP and EPO in bone marrow,peripheral blood and nasal lavage fluid were detected by RT-PCR.Results:Compared to the control group and CCR3 siR.NA therapy group,the nasal mucosa of the PBS therapy group and siRNA therapy group developed epithalaxy.goblet cells hyperplasia,squamous epithelium metaplasia,epithelium necrosis,lamina propria and submucosa gland hyperplasia,vasodilatation,tissue edema,and the characterized eosinophil infiltration.RT-PCR indicated that the CCR3 rnRNA,MBP.ECP and EPC)expression in bone marrow,peripheral blood and nasal lavage fluid of the CCR3 siKNA therapy group was lower than the PBS therapy group and siR.NA therapy group(P<0.05).Conclusions:The RNA interference therapy to CCR3 by local administration pernasal can suppress the process of the development,migration and invasion of the allergic rhinitis eosinophil,thus can reduce the effect of eosinophils and then reduce the inflammation effect of the allergic rhinitis.It may be a new treatment for respiratory tract allergic inflammation.

drug-induced autoimmune liver disease:a diagnostic dilemma of an increasingly reported disease

The aetiology of autoimmune hepatitis(AIH) is uncer-tain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs.AIH usually develops in individuals with a genetic back-ground mainly consisting of some risk alleles of the major histocompatibility complex(HLA).Many drugs have been linked to AIH phenotypes,which sometimes persist after drug discontinuation,suggesting that they awaken latent autoimmunity.At least three clini-cal scenarios have been proposed that refers to drug- induced autoimmune liver disease(DIAILD):AIH with drug-induced liver injury(DILI); drug induced-AIH(DI-AIH); and immune mediated DILI(IM-DILI).In addi-tion,there are instances showing mixed features of DI-AIH and IM-DILI,as well as DILI cases with positive autoantibodies.Histologically distinguishing DILI from AIH remains a challenge.Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however,a detailed standard-ised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diag-nosis between both entities.Growing information on the relationship of drugs and AIH is being available,being drugs like statins and biologic agents more fre-quently involved in cases of DIAILD.In addition,there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepa-totoxicity.Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of

Effects of lysedEnterococcus faecalis FK-23 on experimental allergic rhinitis in a murine model

In the current study, we sought to investigate whether lysed Enterococcus faecalis FK-23 （LFK）, a heat-killed probiotic preparation, attenuated eosinophil influx into the upper airway and had immunomodulatory activity in a murine allergic rhinitis model. Eighteen BALB/c mice were divided into three groups; the ovalbumin （OVA）-sen- sitized/challenged group, which received saline orally for 6 weeks （OVA group）, the OVA-sensitized/challenged group, which received LFK orally for 6 weeks （LFK-fed group）, and the non-sensitized group, which received saline for 6 weeks （saline control group）. Nasal rubbing and sneezing were monitored during the study. After the final challenge, interleukin （IL）-4, interferon （IFN）-y, and OVA-specific IgE levels in the sera and splenocyte culture supernatants were determined, eosinophilic infiltrate into the upper airway was quantified, and splenic CD4~CD25＋ regulatory T cells （Tregs） were examined by flow cytometry. We found that nasal rubbing was sig- nificantly reduced in LFK-fed mice compared to the OVA group on d 27 and 35, and sneezing was significantly inhibited by LFK administration for 35 d. LFK-fed mice had significantly less eosinophil influx into the nasal mucosa than the OVA group. There were no significant differences between the LFK-fed group and OVA group in the serum and splenocyte culture supernatant levels of IL-4, IFN-y, and OVA-specific IgE. Interestingly, the LFK-fed mice had a significantly greater percentage of splenic CD4＋CD25＋ Tregs than OVA group. Our results indicate that oral administration of LFK may alleviate nasal symptoms, reduce nasal eosinophilia, and increase the percentage of CD4＋CD25＋ Tregs in experimental allergic rhinitis.

Practical guidelines for diagnosis and early management of drug-induced liver injury

The spectrum of drug-induced liver injury （DILI） is both diverse and complex. The first step in diagnosis is a suspicion of DILl based on careful consideration of recent comprehensive reports on the disease. There are some situations in which the suspicion of DILI is particularly strong. Exclusion of other possible etiologies according to the pattern of liver injury is essential for the diagnosis. In patients with suspected DILl, diagnostic scales, such as the Councils for International Organizations of Medical Sciences/ Roussel Uclaf Causality Assessment Method （CIOMS/RUCAM） scale, may be helpful for the final diagnosis. Early management of DILl involves prompt withdrawal of the drug suspected of being responsible, according to serum levels of alanine aminotransferase （ALT）, alkaline phosphatase （ALP）, and total bilirubin （T-Bil）. However, as DILI patients may show resolution of liver injury without discontinuation of the drug, it should be carefully evaluated whether the suspected drug should be discontinued immediately with adequate consideration of the importance of the medication.

Association between Promoter Polymorphisms of Interleukin-4 Gene and Allergic Rhinitis Risk: a Meta-analysis

Summary： The relationship of interleukin-4 （IL-4） C-33T and C-590T （C-589T） gene polymorphisms with allergic rhinitis was analyzed. Data about the case control studies of IL-4 gene promoter polymorphisms [C-33T and C-590T （C-589T）] and their association with allergic diseases and correlation between serum IL-4 levels and allergic rhinitis were retrieved. The Stata 12.0 statistical soitvcare was applied to analyze the correlation between IL-4 gene polymorphisms and allergic rhinitis. The meta-analysis result of TT/CC genotype of -590 （-589） polymorphism showed a significant association with allergic diseases [OR=1.93, 95% CI （1.61 2.31）, P=0.00]. Meta-analysis of the TT＋TC versus CC genotype of IL-4 C-33/T polymorphism revealed significant associations with allergic diseases [OR=3.23, 95% CI （1.13-9.25）, P=0.03]. Meanwhile, there was a significant correlation between serum IL-4 levels and allergic rhinitis [OR=2.52, 95% CI-（1.80-3.23）, P=0.00]. IL-4 gene -590 TT genotype may increase the risk of allergic rhinitis and the T allele mutation of -33 might be correlated with aller- gic rhinitis.

Drug-induced liver injury:Is it somehow foreseeable?

The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neosubstances that react abnormally), mainly by cytochromes P-450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.

NAT2＊6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.

Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists

Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.