Detection and incidence of drug-induced liver injuries in hospital: a prospective analysis from laboratory signals

AIMS: Liver damage remains the most frequent type of adverse drug reaction (ADRs) that can lead to the withdrawal of a drug from the market. The abnormal laboratory data identified by computerized hospital information systems can be used in order to improve the detection of ADRs. Our objectives were to assess the detection and incidence of drug-induced liver abnormalities in a university hospital inpatient population and to evaluate the underreporting rate of drug-induced liver injury. METHODS: We conducted a prospective study performed 1 week per month from June to October 1997. We selected patients by a computerized process using biochemistry laboratory data, based on serum enzyme values, alanine aminotransferase (over 2 fold normal) and alkaline phosphatase (over 1.5 fold normal). RESULTS: Among 1976 ALT and 1814 AP assays performed during the period of the study, 156 (7.9%) and 159 (8.8%) tests, respectively, fell into the selected criteria. These concerned 147 patients. Among these patients, 13 (8.8%) cases of drug-induced liver injuries were suspected. Seven cases were asymptomatic. Six cases were classified as serious by these criteria: hospitalization to investigate the cause of health status impairment (4 patients), prolongation of hospitalization (1 patient) and life-threathening (1 patient). Using the hospitalization database, the incidence of drug-induced liver injuries was estimated as 6.6 per 1000 inpatients a week. Only 1 case was reported by physicians in the same period. CONCLUSIONS: Computerization of biochemical data would allow the development of systems to improve detection of drug-induced injury. Moreover, underreporting remains important for such potentially serious ADRs, even in a university hospital.     

Detection and incidence of muscular adverse drug reactions: a prospective analysis from laboratory signals

Aims The awareness of muscular adverse drug reactions (ADRs) increased since the withdrawal of cerivastatin, a HMG-CoA reductase inhibitor, from the market in August 2001. Our objectives were to assess the detection and incidence of muscular ADRs in a University Hospital using biochemical laboratory data and to evaluate the underreporting rate of drug-induced muscular disorders.Methods A prospective study was undertaken at Toulouse University Hospital, France, for 1 week per month from November 2001 to October 2002. Patients were selected by means of a computerized process using biochemical laboratory data based on serum creatine phosphokinase (CPK) values (over twofold normal). Medical records of all selected patients were then consulted.Results During the period of the study, 2017 CPK tests were performed, among which 171 values were over twofold normal corresponding to 129 patients. Because of lack of data, 26 patients were excluded. Among these patients (n=103), 28 cases of muscular ADRs were suspected, 22 of which were detected in outpatient departments. Four patients were totally asymptomatic and five had an increase of CPK over fivefold normal. Nine cases were classified as serious. Withdrawal of suspected drugs were done in 16 cases with regression of ADRs in 13 cases. According to hospitalization data, the incidence of muscular ADRs was estimated as 7.2 (2.6–15.7) per 10,000 inpatients and 9.3 (5.8–14.1) per 10,000 outpatients over 12 weeks. The involved drugs were mainly: statins (46.4%), fibrates (14.3%), antiretrovirals (14.3%), angiotensin-II receptor antagonists (10.7%), immunosuppressants (7.1%) or hydroxychloroquine (7.1). Only two cases, judged as serious, were spontaneously reported by physicians during the same period.Conclusion The results of this survey underline the importance to take into account drug hypothesis in muscular injuries diagnosis.     

Recognition and management of drug-induced blood cytopenias: the example of drug-induced acute neutropenia and agranulocytosis

Background: More than several hundred drugs, toxins, and herbs have been reported to cause blood abnormalities, and drugs account for 20 – 40% of all instances of cytopenias. Objective: In the present paper, we report and discuss the recognition and the management of drug-induced acute neutropenia or agranulocytosis (neutrophil count of < 0.5 × 10⁹/l). Methods: A bibliographic search was performed on the PubMed database of the US National Library of Medicine for articles published from January 1990 to January 2008. Additional not published data of our cohort of drug-induced agranulocytosis in the University Hospital of Strasbourg, France were incorporated in this review. Results/conclusions: Idiosyncratic drug-induced acute neutropenia or agranulocytosis is a serious adverse event due to the frequency of severe infections (such as deep infections, septicemia and septic shock) but modern management with broad spectrum antibiotics and hematopoietic growth factors is likely to improve the prognosis. Given the increased life expectancy, increasing use of medications as a therapeutic modality and subsequent longer exposure to drugs, as well as the development of new agents, healthcare professionals should be aware of this adverse event and its management.     

住院患者药物性肝病的危险因素和可疑药物分析

目的探讨药物性肝病在住院患者人群中的发生率、危险因素和可疑药物。方法基于上海市医院住院患者用药数据库中拥有2次及以上ALT记录的患者人群,以用药后ALT〉60U·L^-1为药物性肝病的评价标准,采用逐步Logistic回归方法分析年龄、性别、服药种类、住院时间和基线ALT值对药物性肝病发生率的影响,并计算引起药物性肝病的可疑药物的似然比。结果：纳入研究的3030例患者中药物性肝病有171例,占5．6l％。服药种类是其危险因素。药物性肝病的可疑药物涉及各个类别的药物,以中药出现的频次最高,其次为主要抗菌药物。有220种可疑药物可能与药物性肝病有关,其中磺胺甲嘿唑、氯胺酮等似然比较高。结论住院患者在合并使用多种药物和应用磺胺甲口恶唑等具有肝毒性药物时应加强肝功能监测,以避免药物性肝病的发生。     

Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic

BACKGROUND: Limited data exist on the proportion of drug-induced liver injury among out-patients seen in a hepatology clinic. AIM: To determine the proportion of drug-induced liver injury cases, and identify the most important agents and the nature of the liver injury. METHODS: A computerized diagnoses database in an out-patient hepatology clinic in a Swedish University hospital was analysed during the period 1995-2005. All suspected drug-induced liver injury cases were causality assessed with the International Consensus Criteria. RESULTS: A total of 1164 cases were seen for the first time during this period. Drug-induced liver injury with at least a possible causal relationship was found in 77 cases (6.6%), 38 (3.3%) of whom were referred for evaluation to the out-patient clinic whereas 3% had a follow-up after hospitalization of drug-induced liver injury. The median age was 58 years, 43 (56%) were females, a hepatocellular pattern was observed in 37 cases (48%), cholestatic in 31 (40%) and mixed in 12%. Antibiotics were the most common agents causing drug-induced liver injury followed by non-steroidal anti-inflammatory drugs, with diclofenac most often responsible for the drug-induced liver injury. CONCLUSIONS: Drug-induced liver injury cases constituted 6% of all out-patients and 3% of referrals and occurred more often in women. Antibiotics and diclofenac were the most common causes of drug-induced liver injury among out-patients.     

住院患者中药物性肾病的可疑药物筛选

目的探讨药物性肾病在我国住院患者人群中发生率及与筛选出其可疑药物。方法利用2009年5月29日至12月31日医院住院患者用药数据库(IDUD)信息,采用数据挖掘技术结合药物流行病学研究方法,计算药物性肾病与可疑药物之间相对危险度。结果共获得药物性肾病的可疑药物130个,其中中药49个。按相对危险度排序,前3位可疑药物分别为扶正化瘀、肾衰宁和精氨酸。结论在住院患者人群中,特别是使用中药的患者,应加强肾功能监测。     

Incidence and risk factors for agranulocytosis in Latin American countries—the Latin Study

PURPOSE: LATIN is a multinational case-control study designed to identify risk factors for agranulocytosis and to estimate the incidence rate of the disease in some Latin American countries. METHODS: Each study site in Brazil, Argentina and Mexico conducted an active search of agranulocytosis patients in hematology clinics and looked for possible associations with drug use. RESULTS: The overall incidence rate was 0.38 cases per 1 million inhabitant-years. Agranulocytosis patients more often took medications already associated with agranulocytosis than controls (p = 0.01), mainly methimazole (OR 44.2, 95% CI 6.8 to infinity). The population attributable risk percentage (etiologic fraction) was 56%. The use of nutrient supplements was more frequent among patients than controls (p = 0.03). CONCLUSIONS: Agranulocytosis seems to be very rare in Latin America. The lower than expected number of cases identified during the study period precluded estimation of the risk associated to individual drugs, with the exception of methimazol. However, this is the longest series of agranulocytosis cases ever gathered in Latin America, and information on drug exposures was collected prospectively. The conclusion is that drug-induced agranulocytosis does not seem to be a major public health problem in the study regions.     

Agranulocytoses médicamenteuses idiosyncrasiques : analyse de 7 ans dans un hôpital universitaire français

IntroductionIdiosyncratic drug-induced agranulocytosis is a rare but potentially serious haematological disorder. The pathophysiological mechanisms are complex and poorly understood. We aimed at investigating agranulocytosis drug related causes from the myelograms with “myeloid maturation arrest” performed in our university hospital over the last seven years.MethodsA retrospective analysis of myelograms collected for agranulocytosis was performed from 1st January 2010 to 31th December 2016. We used the method of Bégaud et al. for drug causality assessment.ResultsAmong the 104 myelograms analysed, 41 agranulocytosis were drug-induced, whose 28 were idiosyncratic. Among these 28 cases, 26 different drugs were involved. Agranulocytosis was a known adverse reaction in the summary of the product characteristics for 24 drugs, mainly associated with undetermined frequency (n = 7). Mean onset latency was 38.1 days after starting the drug (calculated for n = 23 cases) and granulocyte growth factors were used in 50% of cases without shortening the mean delay of blood count recovery. Bone marrow presented hypereosinophilia in 29% of cases. Pharmacovigilance reporting rate was 48%.ConclusionA “maturation arrest” in the myelogram is not pathognomonic for idiosyncratic drug-induced agranulocytosis. This rare event require multidisciplinary care involving haematologists, biologists and pharmacovigilance experts. Agranulocytosis reporting rate was high compared with usual adverse drug reaction reporting rate (5 to 10%), probably related to the potential severity of this event.     

Non‐Chemotherapy‐Induced Agranulocytosis Detected by a Prospective Pharmacovigilance Program in a Tertiary Hospital

We conducted a prospective evaluation of non‐chemotherapy‐induced agranulocytosis (NIA) in a tertiary hospital in Spain. Through our Prospective Pharmacovigilance Program from Laboratory Signals at Hospital, we detected agranulocytosis cases over a period of 42 consecutive months. This report estimates incidence, drug causality, clinical features and outcomes of NIA cases and assesses laboratory differences with respect to non‐NIA. We detected 1349 cases of agranulocytosis in 538 adult patients; of these, 43 cases in 40 patients were caused by non‐chemotherapy drugs. The incidence rate for 10,000 patients during the study period was 2.75 [Poisson confidence interval (CI)‐95%: 0.62–7.22]. The mean (S.D.) age was 48 (21) years. All cases were categorized as serious, because they required hospitalization (28 cases) or prolongation of hospitalization (15 cases). The outcome was recovery without sequela (39 cases), recovery with sequela (one case of toe amputation) or death (three cases, 7%). The most frequent cause of NIA was antimicrobial drugs (19 cases). The highest incidence rate per 10,000 defined daily doses was for cefepime (83.85; Poisson‐CI 95%: 67–102.89). Automatic linear modelling (n = 75, R² = 77.9%) showed a significant inverse association with platelets, alkaline phosphatase, C‐reactive protein, fibrinogen, lactate dehydrogenase; and direct association with mean corpuscular haemoglobin, and haematocrit. A generalized linear model retained platelets, total serum proteins, creatinine and haemoglobin. The findings suggest an immune‐mediated destruction or myeloid toxicity, possibly facilitated by an increase in drug exposure. There might be additional contributing factors, such as nutritional deficiencies or chronic diseases, to develop NIA after exposure to a potentially causative drug.     

Use of administrative hospital database to identify adverse drug reactions in a Pediatric University Hospital

Purpose

The aim of the study was to detect adverse drug reactions (ADRs) in pediatric inpatients using the medical administrative database “Programme de Médicalisation des Systèmes d′Information” (PMSI) and to compare these cases ADRs with those spontaneously reported to a regional PharmacoVigilance (PV) Centre.

Methods

The study was conducted from January 2008 to December 2011 in the Children University Hospital of Toulouse (Midi-Pyrénées, South-west France). From PMSI database, all discharge summaries including selected ICD-10 codes (10th International Classification of Diseases) were analyzed. All ADRs spontaneously reported by the Children Hospital of Toulouse and registered in the French PV Database (FPVDB) were included. The capture–recapture method was applied to estimate the incidence of ADRs.

Results

During the study period, we identified 60 reports from the PMSI database and 200 from the FPVDB. The rate of “serious” ADRs was higher in PMSI reports (74.6 % vs 38.9 %, p?Conclusions Use of PMSI database improves from around 30 % detection of ADRs in children. In comparison with classical pharmacovigilance database, it also allows to detect different ADRs and drugs, thus enhancing safe medicine use for pediatric patients.     

1例β-内酰胺类抗菌药物致中性粒细胞减少的病例分析

1例54岁中年男性因“社区获得性肺炎”接受β-内酰胺类药物治疗3周后,呼吸道症状好转,同时出现中性粒细胞减少。药师考虑与治疗药物相关可能大,建议停止抗感染治疗。患者停药12 d后未经治疗中性粒细胞计数恢复正常,可以确诊为药源性中性粒细胞减少。     

Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors

To determine the role of growth factors in nonchemotherapy drug-induced agranulocytosis, we reviewed 118 published reports of administration of colony-stimulating factors for the disorder. Main outcomes were total duration of neutropenia and mortality. The mean time to neutrophil recovery was 4.6 +/- 3.2 days and 7.7 +/- 5.1 days in patients with a granulocyte count at diagnosis of 0.1-0.5 x 10(3)/mm3 and less than 0.1 x 103/mm3, respectively. The mortality rate was 4.2%. Without therapy with growth factors, the mean time to neutrophil recovery after discontinuation of the offending agent was reported to be 10 +/- 8 days. The mortality rate was 16% in one study. We conclude that hematopoietic growth factors may shorten the duration of neutropenia and reduce mortality in patients with severe drug-induced agranulocytosis.     

新生儿药物不良反应监察

对６５７名新生儿进行药物不良反应的医院内集中监察。监察期间共有６８名新生儿发生药物不良反应７３次，发生率约为１０％。严重的不良反应包括上消化道出血、肾功能衰竭、心律失常、钙盐沉积和肺损害。抗生素、脂肪乳剂、地高辛和镇静药为最常涉及的药物。本课题首次提供前瞻性药物流行病学报告，以促进新生儿安全用药。     

Clinical analysis of 275 cases of acute drug-induced liver disease

In order to analyze the causative drugs, clinical manifestation and pathological characteristics of the patients with acute drug-induced liver disease, from January 2000 to December 2005, 275 cases diagnosed as acute drug-induced liver diseases according to Maria Criterion and hospitalized in Zhongshan Hospital of Fudan University were retrospectively reviewed. Each was determined by drug history, clinical symptoms and signs, laboratory tests and therapeutic effects. In 41 cases, the diagnosis was confirmed by liver biopsy. The proportion of acute drug-induced liver disease among all of the acute liver injuries was annually increased. The most common drugs which induced acute liver injuries were traditional Chinese herb medicine (23.3%, 64/275 cases), antineoplastic (15.3%, 42/275), hormones and other immunosuppressant agents (13.8%, 38/275), antihypertensive drugs and other cardiovascular drugs (10.2%, 28/275), NSAIDs (8.7%, 24/275) respectively. Hepatocellular injury was the predominant type in these cases (132 cases, 48%). The principal clinical manifestation included nausea (54.8%), fatigue (50.2%), jaundice (35.6%). 27.9% patients were asymptomatic. Most patients were cured with good prognosis. The total effective rate was 94.2% after treatment. The clinicians should pay attention to the prevention, diagnosis and therapy of drug-induced liver disease.     

Life-threatening idiosyncratic drug-induced agranulocytosis in elderly patients

Agranulocytosis is a life-threatening disorder in any age, but particularly so in elderly patients who are receiving, on average, a larger number of drugs than younger patients. Drug-induced agranulocytosis still remains a rare event, with an annual incidence rate of approximately 3-12 cases per million population. This disorder frequently occurs as an adverse reaction to drugs, particularly antibacterials, antiplatelet agents, antithyroid drugs, antipsychotics or antiepileptic drugs, and NSAIDs. Although patients experiencing drug-induced agranulocytosis may initially be asymptomatic, the severity of the neutropenia usually translates into the onset of severe sepsis that requires intravenous broad-spectrum antibacterial therapy. In this setting, haematopoietic growth factors have been shown to shorten the duration of neutropenia. Thus, with appropriate management, the mortality rate of idiosyncratic drug-induced agranulocytosis is now 5-10%. However, given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, physicians should be aware of this complication and its management.     

Antipsychotic drugs result in the formation of immature neutrophil leucocytes in schizophrenic patients

Subclinical abnormality of neutrophil populations of patients suffering from schizophrenia and medicated with antipsychotic drugs was evaluated using cellular immaturity as a criterion. Neutrophil maturity of patients and controls was compared by determining mean nuclear lobularity in peripheral blood smears. White blood cell and neutrophil counts were made. Subjects were patients medicated with chlorpromazine (n = 17) or clozapine (n = 48). Controls (n = 58) were healthy, non-medicated clinical and academic staff. Determination of mean lobe number involved assessment of 300 neutrophils per individual. For subject and control groups, means and medians of mean lobe numbers and mean white cell and neutrophil counts were determined. Means for each group were compared using the Mann-Whitney U-test; variances using F ratios. Means of lobe numbers of both patient populations were significantly different (p < 0.0001) compared to controls. Two-thirds of patients had mean lobe numbers outside the control range. Dose-response (mean lobe number) plots were significant for patients medicated with both chlorpromazine and clozapine. White cell and neutrophil counts in patients and controls did not differ significantly. For six patients, mean lobe numbers were obtained before and after medication commenced and all showed lowering of mean lobe number. The mean lobe number of the one patient who subsequently suffered from agranulocytosis was at the low end of the patient range. Thus, patients medicated with antipsychotic drugs typically have immature neutrophils, but normal white cell and neutrophil numbers. This effect is probably drug-induced. Mean lobe number may predict patients at risk from agranulocytosis.     

Spontaneous reports on drug-induced pancreatitis in Denmark from 1968 to 1999

OBJECTIVES: To present an update on drug-induced pancreatitis reported to the Danish Committee on Adverse Drug Reactions. DESIGN: Retrospective study of spontaneous case reports to the Danish reporting system on adverse drug reactions. METHODS: All cases of suspected drug-induced pancreatitis reported to the Danish Committee on Adverse Drug Reactions from 1968 to 1999 were analysed. Three cases were excluded leaving 47 cases for analysis. RESULTS: Drug-induced pancreatitis made up 0. 1% of all the reports to the committee from 1968 to 1999. The proportion seemed to increase and was 0.3% during the last 8 years. The 47 cases corresponded to 0.1% of the number of patients discharged due to pancreatic disease (without cancers) per year in Denmark. Serious courses were frequent as indicated by death and hospitalisation being reported in 4 (9%) and 32 (68%) cases, respectively. Death occurred after valproate (two cases), clomipramine (one case) and azathioprine (one case). Definite relationship was stated for mesalazine (three cases), azathioprine (two cases) and simvastatin (one case) on the basis of re-challenge. A possible or probable causality was considered for a further 30 drugs including 5-acetylsalicylic acid agents, angiotensin-converting enzyme inhibitors, estrogen preparations, didanosine, valproate, codeine, antiviral agents used in acquired immunodeficiency syndrome therapy, various lipid-reducing agents, interferon, paracetamol, griseofulvin, ticlopine, allopurinol, lithium and the MMR (measles" mumps/rubella) vaccination. CONCLUSION: Drug-induced pancreatitis is rarely reported. The incidence may be increasing and the course is often serious. This is the first report on definite simvastatin-induced pancreatitis. Further studies on the pancreotoxic potential of drugs are warranted.     

我院住院患者药源性肾功能损害分析

目的:了解我院住院患者中药源性肾功能损害的情况以指导合理用药。方法:对我院2007年6、8、10月中血清肌酐值异常的102例患者进行回顾性分析。结果:有20例药源性肾功能损害(占19.6%),可疑药物包括脱水药、抗生素、血管紧张素转换酶抑制剂等22种。结论:应严格按适应证选择药物,按药品说明书规定的用法、用量用药。     

127例药物不良反应分析

目的:分析引起不良反应的药物临床表现及防治。方法:回顾性分析临床用药发生不良反应的情况。结果:127例不良反应中,心血管药物77例,占60.63％;其它为内分泌、激素药物22例,占17.32％;抗生素11例,占8.66％;抗癌药3例,占2.36%;其它14例,占11.02％。重症不良反应48例,占37.79％;死亡6例,占4.72％.结论:心血管药物可能引致较严重的不良反应。     

某院消化内科病房40例药物性肝损伤综合分析

目的 探讨药物性肝损伤病例发生的特点.方法 收集2011年1月-2015年12月某医院消化内科病房的药物性肝损伤病例,每例患者填写药品不良反应报告表,详细记录患者性别、年龄、可疑药品使用情况、药物性肝损伤发生及处理情况,并进行临床分型,将所有数据使用Excel软件进行统计分析.结果 共收集药物性肝损伤病例40例,其中女性18例,男性22例;＞45岁的中老年患者占所有发病人数的70％;中草药和中成药导致的药物性肝损伤共有25例,高达62.5％,其他依次为抗感染药物、免疫系统用药、消化系统用药、抗痛风药、心血管系统用药、内分泌系统用药.33例(82.50％)患者用药开始到肝损伤发生的时间在5～90 d.39例患者从停药开始到肝损伤发生的时间≤15 d,只有1例肝血管损伤型超过30 d.32例患者对症治疗后好转,8例由土三七导致的肝小静脉闭塞症无法逆转,留下后遗症.结论 临床药师应积极推动药物性肝损伤的防治工作,协助医师制定合理的药物治疗方案,避免药物滥用,以减少药物性肝损伤的发生.