Drug-induced liver injury: Do we know everything?

Interest in drug-induced liver injury(DILI) has dramatically increased over the past decade, and it has become a hot topic for clinicians, academics, pharmaceutical companies and regulatory bodies. By investigating the current state of the art, the latest scientific findings, controversies, and guidelines, this review will attempt to answer the question: Do we know everything? Since the first descriptions of hepatotoxicity over 70 years ago, more than 1000 drugs have been identified to date, however, much of our knowledge of diagnostic and pathophysiologic principles remains unchanged. Clinically ranging from asymptomatic transaminitis and acute or chronic hepatitis, to acute liver failure, DILI remains a leading causes of emergent liver transplant. The consumption of unregulated herbal and dietary supplements has introduced new challenges in epidemiological assessment and clinician management. As such, numerous registries have been created, including the United States Drug-Induced Liver Injury Network, to further our understanding of all aspects of DILI. The launch of Liver Tox and other online hepatotoxicity resources has increased our awareness of DILI. In 2013, the first guidelines for the diagnosis and management of DILI, were offered by the Practice Parameters Committee of the American College of Gastroenterology, and along with the identification of risk factors and predictors of injury, novel mechanisms of injury, refined causality assessment tools, and targeted treatment options have come to define the current state of the art, however, gaps in our knowledge still undoubtedly remain.

Statin use and the risk of colorectal cancer: A population-based case-control study

AIM: To investigate whether the use of statins is associated with colorectal cancer risk. METHODS: We conducted a population-based case-control study in Taiwan. Data were retrospectively collected from the Taiwan National Health Insurance Research Database. Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of colorectal cancer between the period 2005 and 2008. The controls were matched to cases by age, sex, and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multiple logistic regression. RESULTS: We examined 1156 colorectal cancer cases and 4624 controls. The unadjusted ORs for any statin prescription was 1.10 (95% CI = 0.94-1.30) and the adjusted OR was 1.09 (95% CI = 0.91-1.30). When statin use was categorized by cumulative dose, the adjusted ORs were 0.99 (95% CI = 0.78-1.27) for the group with cumulative statin use below 105 defined daily doses (DDDs); 1.07 (95% CI = 0.78-1.49) for the group with cumulative statin use between 106 and 298.66 DDDs; and 1.30 (95% CI = 0.96-1.75) for the group with cumulative statin use of 298.66 DDDs or more compared with nonusers. CONCLUSION: This study does not provide support for a protective effect of statins against colorectal cancer.

Antibiotic prescribing patterns for upper respiratory tract infections in rural Western China

Objective To explore the prescribing patterns of outpatients receiving antibiotics for upper respiratory tract infections(URTIs)in rural Western China and to identify the correlation in terms of doctors and patients characteristics.Methods Totally 7 678 prescriptions for URTIs were collected from 680 primary health village clinics of 40 counties across 10 provinces of Western China.Two outcome variables were used in the analysis:the occurrence of prescribing at least one antibiotic drug for an URTI and the occurrence of prescribing two or more antibiotics for an URTI.GEE logistic regression models were used to examine the socioeconomic and demographic determinants of the above two outcome variables.Results The percentage of prescribing at least one antibiotic for URTIs was 48.6% while the percentage of prescribing antibiotic combination(two or more antibiotics)was 4.6%.The two measurements of antibiotic utilization differed remarkably among the 10 provinces.Patients diagnosed with tonsillitis and faucitis had higher odds(OR=8.86 for tonsillitis and OR=4.64 for faucitis)of antibiotic prescription than patients with other diagnosis of URTIs.Patients with tonsillitis and faucitis also had higher odds(OR=3.82 for tonsillitis and OR=2.71 for faucitis)of multiple antibiotic prescription than those with other diagnosis of URTIs.The number of drugs per prescription and injection in prescriptions were also significant predictors of antibiotic and multiple antibiotic utilization for URTIs.Conclusion It is concluded that the percentage of antibiotic prescription for URTIs is higher in rural Western China than in most of other countries with available data and that prescriptions of antibiotics for URTIs are associated with residence regions of patients,URTI diagnosis and background information on drug prescription.

Overview of drug induced liver injury in Brazil:What is the role of public health policy on the evidence?

BACKGROUND Adverse drug reactions are responsible for increased costs and morbidity in the health system.Hepatotoxicity can be induced both by non-prescription drugs and by those used for chronic diseases.It is the main cause of safety-related drug marketing withdrawals and could be responsible for irreversible and fatal injuries.AIM To identify and to summarize Brazilian studies reporting the drug-induced liver injury.METHODS A systematic review of Brazilian studies was carried out until June 2020.It was found 32 studies,being 10 retrospective cohorts,12 prospective cohorts,5 crosssectional,3 case-control,one case series and one randomized clinical trial.In most studies were investigated tuberculosis patients followed by other infectious conditions like human immunodeficiency virus(HIV)and hepatitis C virus.The hepatotoxicity ranged from one to 57%,led by isoniazid,rifampicin,and pyrazinamide.Few studies reported algorithm to assess causality.In most studies,there were moderate outcomes and it was necessary drug interruption.However,few severe outcomes,such as chronic liver damage and liver transplantation were reported.RESULTS Twenty-two different criteria for hepatotoxicity were found.The great heterogeneity did not allow a meta-analysis.Standardization of parameter of drug-induced liver injury and greater effort in pharmacovigilance could contribute to learn more about drug-induced liver injury(DILI)’s epidemiology in Brazil.CONCLUSION The development of strategic public health policies seems to have an influence on the DILI scientific evidence in Brazil due to main studies are in HIV and tuberculosis line care,two strategic health policies in Brazil.

Clostridium difficile infection in the community:Are proton pump inhibitors to blame?

Once a nosocomial disease,Clostridium difficile infection(CDI)now appears frequently in the community in the absence of exposure to antibiotics.Prior studies have shown that patients with community-acquired CDI are younger,more likely to be female,and have fewer comorbidities compared to patients with hospital-associated CDI.Because most studies of CDI are hospitalbased,comparatively little is known about communityacquired CDI.The recent study by Chitnis has received widespread attention because it used active surveillance to capture all cases of community-acquired CDI within a large population and assessed key risk factors.The authors found that low-level healthcare exposure and proton pump inhibitor use were common among those with non-antibiotics associated,community-acquired CDI.In this commentary,we discuss the changing epidemiology of community-acquired CDI and the evidence basis for the controversial association between proton pump inhibitors and community-acquired CDI.

Pattern of triptans use: a retrospective prescription study in Calabria, Italy

Triptans are 5-hydroxytryptamine 1 B/1 D receptor agonists used in moderate to severe migraine attacks as first line when non-specific,symptomatic,nonsteroidal anti-inflammatory drugs are not effective.To gain insight in the treatment of migraine in the regional context,this retrospective(from January to August of the years 2017 and 2018)study aimed at monitoring the use of triptans approved by the regional health authority in Calabria.The data demonstrate that the overall treatment of migraine with triptans in the different provinces of Calabria falls in the average regional prescription/dispensation.Interestingly,Crotone showed a trend to an increased amount of defined daily dose/1000 inhabitants per day.The present analysis might stand for homogeneity of treatment of migraineurs in Calabria and highlights the need for better understanding the apparent differences in the local pattern of almotriptan use to improve the appropriateness.

Measuring compliance of package inserts in the Emirate of Abu Dhabi—UAE

Purpose: The aim of this study was to examine if package inserts (PIs) supplied with prescribed medications in the Emirate of Abu Dhabi contain all relevant information to the safe and appropriate use of these medications. Methods: Sixty seven PIs for prescription—only medications were evaluated against a set of safety criteria published from the Ministry of Health. Results: Analyzed PIs showed many deficiencies with regard to the Ministry of Health (MOH) Investigation New Drug Application (INDA) requirements. Particularly of concern were side effects, warnings, use in pregnancy, lactation, and the storage conditions for the product. Conclusions: This study indicated that information relevant to the safe and appropriate use of medications was not uniformly mentioned in the PIs analyzed. To avoid medication errors due to deficits in the current PIs, we recommend regulatory oversight and regulator audits from pharmaceutical company, followed by enhancement of regulations requiring companies to also create patient information leaflets.

Impact of diabetes mellitus on risk of cardiovascular disease and all-cause mortality: Evidence on health outcomes and antidiabetic treatment in United States adults

AIMTo examine the epidemic of diabetes mellitus (DM) and its impact on mortality from all-cause and cardiovascular disease (CVD), and to test the effect of antidiabetic therapy on the mortality in United States adults. METHODS The analysis included a randomized population sample of 272149 subjects ages ≥ 18 years who participated in the National Health Interview Surveys (NHIS) in2000-2009. Chronic conditions (hypertension, DM and CVD) were classified by participants’ self-reports of physician diagnosis. NHIS-Mortality Linked Files, and NHIS-Medical Expenditure Panel Survey Linkage Fileson prescribed medicines for patients with DM were used to test the research questions. χ 2, Poisson and Cox’s regression models were applied in data analysis.RESULTS Of all participants, 22305 (8.2%) had DM. The prevalence of DM significantly increased from 2000 to 2009 in all age groups (P < 0.001). Within an average 7.39 (SD= 3) years of follow-up, male DM patients had 1.56 times higher risk of death from all-cause (HR = 1.56, 95%CI:1.49-1.64), 1.72 times higher from heart disease [1.72 (1.53-1.93)], 1.48 times higher from cerebrovascular disease [1.48 (1.18-1.85)], and 1.67 times higher from CVD [1.67 (1.51-1.86)] than subjects without DM,respectively. Similar results were observed in females. In males, 10% of DM patients did not use any antidiabetic medications, 38.1% used antidiabetic monotherapy, and 51.9% used ≥ 2 antidiabetic medications. These corresponding values were 10.3%, 40.4% and 49.4% in females. A significant protective effect of metformin monotherapy or combination therapy (except for insulin) on all-cause mortality and a protective but non-significant effect on CVD mortality were observed. CONCLUSION This is the first study using data from multiple linkage files to confirm a significant increased prevalence of DM in the last decade in the United States. Patients with DM have significantly higher risk of death from all-cause and CVD than those without DM. Antidiabetic mediations,specifically for metformin use, show a protective effect against all-cause and CVD mortalities.

Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes

There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system(RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials(RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios(HR) regarding the treatment effects of these drugs for cardiovascular disease(CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.

Landscape of DILI-related adverse drug reaction in China Mainland

Drug-induced liver injury(DILI)is a type of bizarre adverse drug reaction(ADR)damaging liver(L-ADR)which may lead to substantial hospitalizations and mortality.Due to the general low incidence,detection of L-ADR remains an unsolved public health challenge.Therefore,we used the data of 6.673 million of ADR reports from January 1st,2012 to December 31st,2016 in China National ADR Monitoring System to establish a new database of L-ADR reports for future investigation.Results showed that totally 114,357 ADR reports were retrieved by keywords searching of liver-related injuries from the original heterogeneous system.By cleaning and standardizing the data fields by the dictionary of synonyms and English translation,we resulted 94,593 ADR records reported to liver injury and then created a new database ready for computer mining.The reporting status of L-ADR showed a persistent 1.62-fold change over the past five years.The national population-adjusted reporting numbers of L-ADR manifested an upward trend with age increasing and more evident in men.The annual reporting rate of L-ADR in age group over 80 years old strikingly exceeded the annual DILI incidence rate in general population,despite known underreporting situation in spontaneous ADR reporting system.The percentage of herbal and traditional medicines(H/TM)L-ADR reports in the whole number was 4.5%,while 80.60%of the H/TM reports were new findings.There was great geographical disparity of reported agents,i.e.more cardiovascular and antineoplastic agents were reported in higher socio-demographic index(SDI)regions and more antimicrobials,especially antitubercular agents,were reported in lower SDI regions.In conclusion,this study presented a large-scale,unbiased,unified,and computer-minable L-ADR database for further investigation.Age-,sex-and SDI-related risks of L-ADR incidence warrant to emphasize the precise pharmacovigilance policies within China or other regions in the world.