Luisa Ibáñez

Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury is Influenced by Multiple HLA Class I and II Alleles

BACKGROUND & AIMS Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. METHODS We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. RESULTS AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)). CONCLUSIONS Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.

Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents.

AbstractAim: The relative gastrointestinal toxicity of NSAIDs in normal clinical practice is unknown. The aim of this study was to estimate the risk of upper gastrointestinal bleeding associated with NSAIDs and analgesics, with special emphasis on those agents that have been introduced in recent years. Design: Multicentre case-control study. Patients: All incident community cases of upper gastrointestinal bleeding from a gastric or duodenal lesion in patients aged >18 years of age (4309 cases). After secondary exclusions, 2813 cases and 7193 matched controls were included in the analysis. Setting: Eighteen hospitals in Spain and Italy with a total study experience of 10 734 897 person-years. Main Outcome Measure: Odds ratios of upper gastrointestinal bleeding for each drug, with adjustment for potential confounders. For each individual drug the reference category was defined as those not exposed to the drug. Results: The incidence of upper gastrointestinal bleeding was 401.4 per million inhabitants aged >18 years. Thirty-eight percent of cases were attributable to NSAIDs. Individual risks for each NSAID were dose dependent. Ketorolac was associated with the highest risk estimate (24.7; 95% CI 8.0, 77.0). For newer NSAIDs, the risks were as follows: aceclofenac 1.4 (95% CI 0.6, 3.3), celecoxib 0.3 (95% CI 0.03, 4.1), dexketoprofen 4.9 (95% CI 1.7, 13.9), meloxicam 5.7 (95% CI 2.2, 15.0), nimesulide 3.2 (95% CI 1.9, 5.6) and rofecoxib 7.2 (95% CI 2.3, 23.0). The risk was significantly increased in patients with a history of peptic ulcer and/or upper gastrointestinal bleeding, and in those taking antiplatelet drugs. Conclusions: NSAID-induced upper gastrointestinal bleeding is a common cause of hospital admission. Apart from the patient’s history of peptic ulcer, its risk depends on the particular drug and its dose, and on concomitant treatments. Our results do not confirm that greater selectivity for COX-2 confers less risk of upper gastrointestinal bleeding.

Agranulocytosis associated with dipyrone (metamizol)

ObjectivesReported estimates of the risk of agranulocytosis associated with metamizol have varied by several orders of magnitude. We assessed this association in a large database for the surveillance of blood dyscrasias.MethodsSince 1980, all laboratory units of haematology in a defined area (3.3–4.1×106 inhabitants) contribute to the ascertainment of all cases of agranulocytosis meeting strict diagnostic criteria. These cases of patients with agranulocytosis and sex-, age-, hospital- and date-matched controls were interviewed using a structured questionnaire about previous drug exposures, and relative risks were calculated for several categories of exposure to metamizol.ResultsAfter a total follow-up of 78.73×106 person-years, 273 community cases of agranulocytosis had been found—of which 96 were excluded for various reasons and 177 were included in the case-control analysis—and were compared with 586 matched controls. Thirty cases of agranulocytosis (16.9%) and nine controls (1.5%) had been exposed to metamizol during the week before the index day. The adjusted relative risk was 25.8 [95% confidence interval (CI), 8.4–79.1], and the attributable incidence was 0.56 (0.4–0.8) cases per million inhabitants and per year. The risk disappeared after more than 10 days since the last dose of metamizol, and it increased with duration of use. Those with agranulocytosis exposed to metamizol had taken the drug for longer periods than the exposed controls. Compared with the cases recently reported from Sweden, the duration of use of metamizol by our exposed cases was substantially shorter, and the use of concomitant medications potentially causing agranulocytosis was lower.DiscussionIn our milieu, agranulocytosis attributable to metamizol is rare. Geographical disparities in its risk estimate can be partly explained by differences in its patterns of use, in terms of dose, duration and concomitant medications.

Upper Gastrointestinal Bleeding Associated With Antiplatelet Drugs

Background  The risk of major upper gastrointestinal bleeding associated with various antiplatelet drugs and the protection conferred by gastroprotective agents are not well defined.

Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs

BACKGROUND/AIMS Acute serious liver disease which is unrelated to infectious, obstructive, or metabolic disease is uncommon. Many drugs have been implicated. Data on its epidemiology are scarce. We performed a population-based prospective study of acute serious liver disease in Catalonia (Spain). METHODS A collaborating hospital network was set up. All patients with acute serious liver disease and negative viral hepatitis serological markers, without an obvious cause of liver disease, were included. RESULTS The incidence of acute serious liver disease was 7.4 per 10(6) inhabitants per year (95% CI; 6.0-8.8), which increased with age. The incidence of hepatocellular acute serious liver disease (3.84 per 10(6) per year) was greater than that of cholestatic and mixed patterns. The case-fatality ratio was 11.9% and mortality 0.8 per million person-years. The risk of death was similar among patients with hepatocellular and cholestatic patterns. Non-steroidal antiinflammatory drugs, analgesics, and antibacterials were the most frequently used drugs. CONCLUSIONS Acute serious liver disease which is unrelated to infectious, obstructive, or metabolic disease is rare. Its incidence increases with age. The prognosis of cholestatic acute serious liver disease does not significantly differ from that of the hepatocellular pattern. Non-steroidal antiinflammatory drugs, analgesics, and antibacterials were the most common drugs likely to be responsible for acute liver disease.

Epidemiology of aplastic anemia : a prospective multicenter study

Aplastic anemia is a rare disease whose incidence varies considerably worldwide. In this study conducted in the metropolitan area of Barcelona, the overall incidence was 2.34 per million inhabitants per year. The survival rate at 2 years was 57%, confirming the severity of this condition. See related perspective article on page 489. Background Aplastic anemia is a rare and severe disease. Its incidence varies considerably worldwide. We aimed at describing the epidemiology of this disease, including the incidence, mortality and survival trends, in a well-defined population. Design and Methods Since 1980, a case-control surveillance study of aplastic anemia has been carried out by a cooperative group, in the metropolitan area of Barcelona. Inclusion is dependent on the patient having at least two of the following features: white blood cell count ≤3.5×109/L, platelet count ≤50×109/L, hemoglobin <10 g/L or hematocrit of <30%; when only one of these last two criteria is fulfilled, a reticulocyte count of ≤30×109/L is also required. The bone marrow biopsy has to be compatible with the diagnosis of aplastic anemia. Results Between 1980 and 2003, a total of 235 cases of aplastic anemia were identified. The overall incidence was 2.34 per million inhabitants per year and the incidence increased with age. Most of the cases were classified as severe or very severe aplastic anemia. Survival rates at 3 months, and at 2 and 15 years after the diagnosis were 73%, 57%, and 51%, respectively. Advanced age and more severe disese at the time of diagnosis were associated with a lower survival rate. There was a trend to a better 2-year survival rate among patients treated with bone marrow transplantation. Forty-nine cases (20.8%) were exposed to drugs reported to be associated with aplastic anemia, and 21 (8.9%) to toxic agents. Conclusions The incidence of aplastic anemia in Barcelona is low but the case fatality rate is high. Advanced age and severe disease at the time of diagnosis were associated with decreased survival.

Adverse Drug Reactions Leading to Hospital Admission

SummaryThis article describes the implementation of a simple method of drug surveillance set up at a hospital emergency ward. From a total of 48678 patients admitted, the medical records of those presenting with one or more of a pre-established list of admission diagnoses (n = 7728; 15.8%) were checked. Of these 554 (1.1%) were diagnosed as experiencing an adverse drug reaction. When the medical record suggested an adverse drug reaction, drugs taken before admission were ascertained by interviewing the patients with a structured questionnaire.After excluding upper gastrointestinal bleeding (226 cases) and certain bone marrow blood dyscrasias (42 cases), 286 patients with drug-induced events leading to hospital admission were identified in 2 years. Fatal adverse drug reactions, previously undescribed reactions, and some specific examples, such as digoxin-amiodarone interaction, drug-induced pancreatitis, nicardipine-induced AV block, severe skin reactions, and NSAID-induced bronchospasm, are described.Basically, this method consists of assembling series of cases systematically, and is therefore devoid of selective bias. In addition, it allows a more indepth clinical and anamnesic study of specific diseases, as compared with voluntary reporting.

Risk of Upper Gastrointestinal Bleeding and the Degree of Serotonin Reuptake Inhibition by Antidepressants

AbstractBackground and objective: Selective serotonin reuptake inhibitor (SSRI) antidepressants can inhibit uptake of serotonin by platelets, and their use may predispose patients to bleeding. Case reports and observational studies from databases have suggested an association between the use of SSRIs and gastrointestinal bleeding. Their risk appears to be increased if they are concurrently used with aspirin (acetylsalicylic acid) or with other NSAIDs. With the aim of establishing the risk of major upper gastrointestinal bleeding associated with various groups of drugs, we performed a multicentre case-control study. We present the results related to the use of antidepressants by the degree of serotonin reuptake inhibition they induce, the selectivity at monoamine transporters and the dose. Methods: A population-based multicentre case-control study in 18 hospitals in Spain and in Italy, including 2813 incident cases of upper gastrointestinal bleeding and 7193 matched controls. Regression analyses are based on 2783 cases and 7058 controls because of missing variable data. Odds ratios (ORs) of upper gastrointestinal bleeding for antidepressant drugs grouped by affinity for the serotonin transporter, selectivity and dose, with adjustment for potential confounders were estimated. Results: Overall, 84 (3.0%) cases and 160 (2.2%) controls had used a high-affinity serotonin reuptake inhibitor (SRI) antidepressant. Their use in the 7 days prior to the index day was not associated with a substantially increased risk of upper gastrointestinal bleeding (OR = 1.24; 95% CI 0.88, 1.76). Forty-one (1.5%) cases and 26 (0.4%) controls had concurrently used a high-affinity SRI antide-pressant and an NSAID. The OR of upper gastrointestinal bleeding among these concurrent users (8.32; 95% CI 4.69, 14.76) did not differ from that in users of NSAIDs only (7.82; 95% CI 6.79, 9.00). No significant association was found between the use of SSRIs and the risk of upper gastrointestinal bleeding, neither with the degree of affinity for the serotonin transporter, by the selectivity of each individual agent (101 cases [3.6%] vs 192 controls [2.7%]; OR = 1.23; 95% CI 0.90, 1.68), nor by dose. Conclusions: The risk of upper gastrointestinal bleeding is not increased by the use of SRIs. An interaction with coadministered NSAIDs was not observed. If there is a risk associated to these drugs, it seems to be low and not an important cause of hospital admission due to upper gastrointestinal bleeding. However, additional studies may be warranted in subgroup populations at potentially increased risk of bleeding, such as older adults and men.

Risk of acute liver injury associated with the use of drugs: a multicentre population survey.

Background  Acute liver injury of uncertain aetiology is often drug related and quantitative information about the associated risk is scarce.

Selective Serotonin Reuptake Inhibitors and Gastrointestinal Bleeding: A Case-Control Study

Background Selective serotonin reuptake inhibitors (SSRIs) have been associated with upper gastrointestinal (GI) bleeding. Given their worldwide use, even small risks account for a large number of cases. This study has been conducted with carefully collected information to further investigate the relationship between SSRIs and upper GI bleeding. Methods We conducted a case-control study in hospitals in Spain and in Italy. Cases were patients aged ≥18 years with a primary diagnosis of acute upper GI bleeding diagnosed by endoscopy; three controls were matched by sex, age, date of admission (within 3 months) and hospital among patients who were admitted for elective surgery for non-painful disorders. Exposures to SSRIs, other antidepressants and other drugs were defined as any use of these drugs in the 7 days before the day on which upper gastrointestinal bleeding started (index day). Results 581 cases of upper GI bleeding and 1358 controls were considered eligible for the study; no differences in age or sex distribution were observed between cases and controls after matching. Overall, 4.0% of the cases and 3.3% of controls used an SSRI antidepressant in the week before the index day. No significant risk of upper GI bleeding was encountered for SSRI antidepressants (adjusted odds ratio, 1.06, 95% CI, 0.57–1.96) or for whichever other grouping of antidepressants. Conclusions The results of this case-control study showed no significant increase in upper GI bleeding with SSRIs and provide good evidence that the magnitude of any increase in risk is not greater than 2.