Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate.

BACKGROUND & AIMS: Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS). METHODS: Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases. RESULTS: Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10-7), coding for an aminopeptidase involved in antigen presentation. The lead eQTL single nucleotide polymorphism, rs1363907 (G), was associated with AC-DILI risk in the discovery (odds ratio [OR], 1.68; 95% CI, 1.23-1.66; P = 1.7 × 10-7) and validation cohorts (OR, 1.2; 95% CI, 1.04-2.05; P = .03), following a recessive model. We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19; 95% CI, 2.09-8.36; P = 4.9 × 10-5) and validation (OR, 7.78; 95% CI, 2.75-21.99; P = .0001) cohorts. GRS, incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non-AC-DILI control cohorts. GRS was the most significant predictor in a regression model containing known AC-DILI clinical risk characteristics and significantly improved the predictive model. CONCLUSIONS: We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.

Incidence of cirrhosis in Iceland-impact of the TraP HepC nationwide HCV elimination program.

OBJECTIVE: In 2016, a nationwide elimination program for hepatitis C virus (HCV) was initiated in Iceland, entitled Treatment as Prevention for Hepatitis C (TraP HepC), providing unrestricted access to antiviral treatment. The aims were to describe the changes in etiology and epidemiology of cirrhosis in Iceland and to assess the trends in HCV-related cirrhosis following TraP HepC. METHODS: The study included all patients newly diagnosed with cirrhosis in 2016-2022. Diagnosis was based on liver elastography, histology, or 2 of 4 criteria: cirrhosis on imaging, ascites, varices, or elevated international normalized ratio (INR). RESULTS: Over the study period, 342 new cirrhosis patients were identified, 223 (65%) males, median age 62 years. The crude overall incidence was 13.8 cases per 100,000 inhabitants annually. The most common etiologies were alcohol-related liver disease (ALD) (40%), metabolic dysfunction-associated steatotic liver disease (MASLD) (28%), and HCV with or without alcohol overconsumption (15%). The number of HCV cirrhosis cases was unusually high in 2016 (n = 23) due to intensified case-finding, but decreased significantly over the study period (p < 0.001) to n = 1 (2021) and n = 2 (2022). The overall 5-year survival was 55% (95% CI 48.9-62.3%). The most common causes of death were hepatocellular carcinoma (26%) and liver failure (25%). CONCLUSION: During the past two decades, the incidence of cirrhosis has increased extraordinarily in Iceland, associated with increased alcohol consumption, obesity, and HCV. ALD and MASLD now collectively make up two thirds of cases in Iceland. Following a nationwide elimination program, incidence of HCV cirrhosis has dropped rapidly in Iceland.

Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

The Evolving Profile of Idiosyncratic Drug-Induced Liver Injury.

Idiosyncratic drug-induced liver injury (DILI) is an infrequent but important cause of liver disease. Newly identified causes of DILI include the COVID vaccines, turmeric, green tea extract, and immune checkpoint inhibitors. DILI is largely a clinical diagnosis of exclusion that requires evaluation for more common causes of liver injury and a compatible temporal association with the suspect drug. Recent progress in DILI causality assessment includes the development of the semi-automated revised electronic causality assessment method (RECAM) instrument. In addition, several drug-specific HLA associations have been identified that can help with the confirmation or exclusion of DILI in individual patients. Various prognostic models can help identify the 5%-10% of patients at highest risk of death. Following suspect drug cessation, 80% of patients with DILI fully recover, whereas 10%-15% have persistently abnormal laboratory studies at 6 months of follow-up. Hospitalized patients with DILI with an elevated international normalized ratio or mental status changes should be considered for N-acetylcysteine therapy and urgent liver transplant evaluation. Selected patients with moderate to severe drug reaction with eosinophilia and systemic symptoms or autoimmune features on liver biopsy may benefit from short-term corticosteroids. However, prospective studies are needed to determine the optimal patients and dose and duration of steroids to use. LiverTox is a comprehensive, freely accessible Web site with important information regarding the hepatotoxicity profile of more than 1000 approved medications and 60 herbal and dietary supplement products. It is hoped that ongoing "omics" studies will lead to additional insight into DILI pathogenesis, improved diagnostic and prognostic biomarkers, and mechanism-based treatments.

Warfarin Is Associated With Higher Rates of Upper But Not Lower Gastrointestinal Bleeding Compared with Direct Oral Anticoagulants: A Population-Based Propensity-Weighted Cohort Study.

BACKGROUND AND AIMS: While overall gastrointestinal bleeding (GIB) rates have been extensively compared between warfarin and direct oral anticoagulants (DOACs), it is still unclear whether upper and lower GIB rates differ between these types of drugs. This study aimed to compare upper and lower GIB rates between warfarin and DOACs in a nationwide cohort. METHODS: Data on all patients in Iceland who received a prescription for oral anticoagulation from 2014 to 2019 were collected and their personal identification numbers linked to the electronic medical record system of the National University Hospital of Iceland and the 4 regional hospitals in Iceland. Inverse probability weighting was used to yield balanced study groups and rates of overall, major, upper, and lower GIB were compared using Cox regression. All GIB events were manually confirmed by chart review. RESULTS: Warfarin was associated with higher rates of upper GIB (1.7 events per 100 person-years vs 0.8 events per 100 person-years; hazard ratio [HR], 2.12; 95% confidence interval [CI], 1.26-3.59) but similar rates of lower GIB compared with DOACs. Specifically, warfarin was associated with higher rates of upper GIB compared with apixaban (HR, 2.63; 95% CI, 1.35-5.13), dabigatran (5.47; 95% CI, 1.87-16.05), and rivaroxaban (HR, 1.74; 95% CI, 1.00-3.05). Warfarin was associated with higher rates of major GIB compared with apixaban (2.3 events per 100 person-years vs 1.5 events per 100 person-years; HR, 1.79; 95% CI, 1.06-3.05), but otherwise overall and major GIB rates were similar in warfarin and DOAC users. CONCLUSIONS: Warfarin was associated with higher rates of upper but not overall or lower GIB compared with DOACs. Warfarin was associated with higher rates of major GIB compared with apixaban.

A revised electronic version of RUCAM for the diagnosis of DILI.

BACKGROUND AND AIMS: Roussel Uclaf Causality Assessment Method (RUCAM) for DILI has been hindered by subjectivity and poor reliability. We sought to improve the RUCAM using data from the Drug-Induced Liver Injury Network (DILIN) and the Spanish DILI Registry, published literature, and iterative computer modeling. APPROACH AND RESULTS: RUCAM criteria were updated, clarified, and computerized. We removed criteria 3 (risk factors) for lack of added value and criteria 4 because we felt it more useful to assess each drug separately. Criteria 6 (drug-specific risk) was anchored to LiverTox likelihood scores. Iterative testing in subsets of 50-100 single-agent, nonherbal cases from both registries was done to optimize performance. We used classification tree analysis to establish diagnostic cutoffs for this revised electronic causality assessment method (RECAM) and compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 DILIN, 96 Spanish DILI). Area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for RECAM and RUCAM. However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, p = 0.14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, p = 0.02; 65 vs. 48 for unlikely/excluded, p = 0.08) than RUCAM diagnostic categories. CONCLUSIONS: RECAM is an evidence-based update that is at least as capable as RUCAM in diagnosing DILI compared with expert opinion but is better than RUCAM at the diagnostic extremes. RECAM's increased objectivity and clarity will improve precision, reliability, and standardization of DILI diagnosis, but further refinement and validation in other cohorts are needed.

A new framework for advancing in drug-induced liver injury research. The Prospective European DILI Registry.

BACKGROUND & AIMS: No multi-national prospective study of drug-induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short-term outcomes of the cases and controls is reported. METHODS: Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016-2021. DILI cases or non-DILI acute liver injury controls following causality assessment were enrolled. RESULTS: Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre-existing liver disease. DILI cases and non-DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin-clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug-induced autoimmune-like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver-related death), and another six received liver transplantation. CONCLUSIONS: In this first multi-national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI.

Ischemic Pancreatitis Is an Important Cause of Acute Pancreatitis in the Intensive Care Unit.

BACKGROUND: Ischemic pancreatitis (IP) has mainly been described in case reports. The aims of the study were to assess the frequency, clinical characteristics and outcomes in patients with IP among patients hospitalized in the intensive care unit (ICU) for acute pancreatitis (AP). METHODS: All patients with first time AP between 2011 and 2018 in the ICU of Landspitali Hospital, Iceland were retrospectively included. IP as an etiology required a clinical setting of circulatory shock, arterial hypotension, hypovolemia and/or arterial hypoxemia [PaO 2 of 60 mm Hg (8.0 kPa), or less] before the diagnosis of AP without prior history of abdominal pain to this episode. Other causes of AP were ruled out. IP patients were compared with patients with AP of other etiologies, also hospitalized in the ICU. RESULTS: Overall 67 patients with AP were identified (median age 60 y, 37% females), 31% idiopathic, 24% alcoholic, 22% IP, 15% biliary, and 8% other causes. Overall, 15 (22%) fulfilled the predetermined criteria for IP, 9 males (64%), median age 62 years (interquartile range: 46 to 65). IP was preceded mainly by systemic shock (73%). Other causes included dehydration, hypoxia, or vessel occlusion to the pancreas. Necrosis of the pancreas was rare with one patient requiring pancreatic necrosectomy. Inpatient mortality was higher among patients with IP than in other patients with AP (33% vs. 14%, P =0.12). CONCLUSIONS: IP was found in a significant proportion of AP patients hospitalized in the ICU. The main causes of IP were systemic shock and hypoxia. IP was associated with ∼30% mortality.

Liver injury in patients with COVID-19 in comparison to patients with the pandemic influenza A (H1N1) 2009: a population-based study.

BACKGROUND: Elevated liver tests in patients with COVID-19 are widely reported. Population-based studies utilizing a validated analysis of drug-induced liver injury (DILI), with a control group of other viral illnesses and follow-up are largely lacking. MATERIALS AND METHODS: All hospitalized patients in Iceland with SARS-CoV-2 in 2020 and pandemic influenza A (H1N1) in 2009 were included in this retrospective, population-based study. Liver tests were compared between the two groups and the correlation to inflammatory markers and persistence of alanine aminotransferase (ALT) elevations were assessed. Potential DILI cases were reviewed using the Roussel Uclaf Causality Assessment Method (RUCAM). RESULTS: 225 SARS-CoV-2-positive and 73 influenza A (H1N1)-positive patients were included. Liver test values were similar between the groups, except for aspartate aminotransferase (AST) which was significantly lower in COVID-19, with a mean difference of 26 U/L (95%CI 4.2-47). Ferritin elevation was positively correlated with ALT, AST and alkaline phosphatase. No patient had persistently elevated ALT in COVID-19 and none had a probable DILI. Only 3 patients had a possible DILI according to the RUCAM. CONCLUSIONS: Elevated liver enzymes are not specific for COVID-19. Hyperferritinemia was associated with elevated liver tests. DILI was very rare in COVID-19 and an unlikely cause of elevated liver enzymes in COVID-19. Abnormal liver tests are nonpersistent and generally not clinically important in these patients.

Long-term sequelae of drug-induced liver injury.

Drug-induced liver injury (DILI) has a very variable clinical and biochemical phenotype and differs widely in severity, from mild injury to life-threatening liver failure. Chronic injury has also been reported to occur at a variable frequency, ranging from 3.4% to 39%, 6-12 months after discontinuing the implicated agent. This wide range is probably related to various definitions of chronic liver injury and variable selection of patients. The long-term sequalae of this chronic injury in terms of morbidity and mortality are unclear, although rare vanishing bile duct syndrome is associated with an unfavourable prognosis, with increased risk of chronic liver failure and need for liver transplantation. Other forms of long-term sequalae associated with DILI are progressive fibrosis, autoimmune-like hepatitis, secondary sclerosing cholangitis, sinusoidal obstruction syndrome and, as a common final stage, the development of cirrhosis, portal hypertension and its complications. Immune checkpoint inhibitors, which can cause an autoimmune-like phenotype have also recently been shown to cause sclerosing cholangitis with cytotoxic T CD8+ cell infiltration in biliary tracts. DILI has been shown to have a significant impact on health-related quality of life but very little is known about its psychological consequences in the long-term. Further investigations with structured long-term follow-up and periodic quality of life surveys are needed to assess the impact of DILI on psychological outcomes, particularly in those with chronic sequelae.

Warfarin is associated with higher rates of epistaxis compared to direct oral anticoagulants: A nationwide propensity score-weighted study.

BACKGROUND: Although epistaxis is one of the most common side effects of oral anticoagulation, it is unclear whether epistaxis rates vary between different oral anticoagulants (OAC). OBJECTIVE: To compare rates of clinically relevant epistaxis between OAC. METHODS: Epistaxis event rates were compared between new users of apixaban, dabigatran, rivaroxaban, and warfarin in a nationwide population-based cohort study over a 5-year study period, 2014-2019. Data was collected from the Icelandic Medicine Registry and the five major hospitals in Iceland. Inverse probability weighting (IPW) was used to yield balanced baseline characteristics, and epistaxis rates were compared using Kaplan-Meier survival estimates and Cox regression. RESULTS: During the study period, 2098 patients received apixaban, 474 dabigatran, 3106 rivaroxaban, and 1403 warfarin. In total, 93 patients presented with clinically relevant epistaxis, including 11 (12%) major epistaxis events and one fatal epistaxis episode. Furthermore, seven patients (9%) with non-major epistaxis later presented with major bleeding during the follow-up period. Warfarin use was associated with higher rates of epistaxis compared to apixaban (2.2 events per 100-person years (events/100-py) vs. 0.6 events/100-py, hazard ratio [HR] 4.22, 95% confidence interval [CI] 2.08-8.59, p < 0.001), rivaroxaban (2.2 events/100-py vs. 1.0 events/100-py, HR 2.26, 95% CI 1.28-4.01, p = 0.005), and dabigatran (2.2 events/100-py vs. no events, HR n/a, p < 0.001). CONCLUSION: Warfarin treatment was associated with higher rates of clinically relevant epistaxis compared to direct oral anticoagulants.

Population pharmacokinetics of esomeprazole in patients with preterm preeclampsia.

Esomeprazole is a proton pump inhibitor being investigated for treatment of preeclampsia. Esomeprazole pharmacokinetics during pregnancy are unknown. We used data from 10 pregnant participants with preterm preeclampsia, and 49 non-pregnant participants to develop a population pharmacokinetic model of esomeprazole. A two-compartment model described the data well. In pregnant participants after single dose, clearance was 42.2% (14.9-61.6%) lower compared to non-pregnant, most likely due to inhibition of CYP2C19. In non-pregnant participants after repeated dosing, clearance was 54.9% (48.2-63.5%) lower in extensive metabolizers and bioavailability was 33% (10.0-52.0%) higher compared to single dosing, which could be due to autoinhibition of CYP2C19. During pregnancy, the CYP2C19 autoinhibition effect with repeated dosing is expected to lead to much lower increase in exposure compared to non-pregnant individuals, since CYP2C19 is already inhibited due to pregnancy.

Prevalence, clinical characteristics and outcomes of hypoxic hepatitis in critically ill patients.

BACKGROUND: Hypoxic hepatitis (HH) is an important clinical entity in patients in the intensive care unit (ICU). The aims of the study were to assess the etiology, clinical characteristics and outcomes of HH in the ICU of a tertiary hospital. Secondary aim was to analyze the effects of concomitant ischemia in other organs than the liver. METHODS: All patients with HH, 2011-2018, in a university hospital ICU were included. Data were collected on etiology, relevant clinical data and outcome. HH was defined by an increase in aminotransferases ≥10 times the upper limit of normal within 48 h from a clinical event of cardiac, circulatory or respiratory failure. Other causes of liver cell necrosis were excluded. RESULTS: Of 9,931 patients hospitalized in the ICU, 159 (1.6%) fulfilled criteria for HH. In-hospital mortality occurred in 85 (53%) and 60 (38%) survived one year. Median ICU stay was five days (interquartile range (IQR) 3-10) and median hospital stay 16 days (IQR 7-32). Shock (48%), cardiac arrest (25%) and hypoxia (13%) were the most common causes of HH. Acute kidney injury (81%), rhabdomyolysis (50%), intestinal ischemia (6%) and ischemic pancreatitis (3%) occurred concomitantly. Age (odds ratio (OR) 1.05 (95% CI 1.02-1.09)), serum lactate (OR 2.61 (95% CI 1.23-5.50)) and lactate dehydrogenase (OR 1.14 (95% CI 1.02-1.27)) were predictors of mortality. CONCLUSIONS: Hypoxic hepatitis was related to shock in approximately 50% of cases and associated with high in-hospital mortality. HH was commonly associated with ischemia in other organs. In-hospital mortality was associated with age, lactate and LD.

Causes of gastrointestinal bleeding in oral anticoagulant users compared to non-users in a population-based study.

BACKGROUND/AIMS: Causes of gastrointestinal bleeding (GIB) in patients on oral anticoagulants (OACs) are not well established. The aims of the study were to compare the causes of GIB in patients on OACs and those not on OAC therapy. METHODS: A nationwide study of all GIB events in patients on OACs in Iceland from 2014-2019 was conducted. Bleeding events were obtained through ICD-10 codes and review of endoscopy databases, confirmed by review of medical records. For comparison, patients not on OACs from previous Icelandic population-based studies were used. RESULTS: Among 752 GIB events in 12,005 patients on OACs, 273 (1.9%) had verified upper and 391 (2.7%) had verified lower GIB. For lower GIB, multivariate analysis showed that OAC users were more likely to have colonic polyps (OR 6.6, 95% CI: 2.4 - 17.8, p < .001) or colorectal cancer (OR 3.7, 95% CI: 2.0 - 7.0, p < .001) but less likely to have ischemic colitis (OR 0.11, 95% CI: 0.04 - 0.26, p < .001). For upper GIB, bleeding from mucosal erosions (OR 4.0 95% CI: 2.5 - 7.9, p < .001) and angiodysplasia (OR 3.6, 95%CI: 1.5 - 8.6, p = .003) were more common in OAC users. CONCLUSIONS: A high proportion of GIB caused by colonic polyps and colorectal cancer among OAC patients indicates that OACs treatment may facilitate cancer diagnosis. The low proportion of ischemic colitis among those on OACs suggests that OACs provide a protective effect against ischemic colitis. OACs seem to increase the bleeding from angiodysplasia and mucosal erosive disease.

Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants : A Nationwide Propensity Score-Weighted Study.

BACKGROUND: Gastrointestinal bleeding (GIB) rates for direct oral anticoagulants (DOACs) and warfarin have been extensively compared. However, population-based studies comparing GIB rates among different DOACs are limited. OBJECTIVE: To compare rates of GIB among apixaban, dabigatran, and rivaroxaban. DESIGN: Nationwide population-based cohort study. SETTING: Landspítali-The National University Hospital of Iceland and the 4 regional hospitals in Iceland. PATIENTS: New users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. MEASUREMENTS: Rates of GIB were compared using inverse probability weighting, Kaplan-Meier survival estimates, and Cox regression. RESULTS: In total, 2157 patients receiving apixaban, 494 patients receiving dabigatran, and 3217 patients receiving rivaroxaban were compared. For all patients, rivaroxaban had higher overall rates of GIB (3.2 vs. 2.5 events per 100 person-years; hazard ratio [HR], 1.42 [95% CI, 1.04 to 1.93]) and major GIB (1.9 vs. 1.4 events per 100 person-years; HR, 1.50 [CI, 1.00 to 2.24]) compared with apixaban. Rivaroxaban also had higher GIB rates than dabigatran, with similar point estimates, although the CIs were wider and included the possibility of a null effect. When only patients with atrial fibrillation were included, rivaroxaban was associated with higher rates of overall GIB than apixaban (HR, 1.40 [CI, 1.01 to 1.94]) or dabigatran (HR, 2.04 [CI, 1.17 to 3.55]). Dabigatran was associated with lower rates of upper GIB than rivaroxaban in both analyses. LIMITATIONS: Unmeasured confounding and small subgroup analyses. CONCLUSION: Rivaroxaban was associated with higher GIB rates than apixaban and dabigatran regardless of treatment indication. PRIMARY FUNDING SOURCE: Icelandic Centre for Research and Landspítali-The National University Hospital of Iceland.

Prevention and management of idiosyncratic drug-induced liver injury: Systematic review and meta-analysis of randomised clinical trials.

Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is challenging. This systematic review aims to summarise the design and findings of RCTs in the prevention and management of idiosyncratic DILI. A systematic literature search up to January 31st, 2020 was performed. Recognised scales were used to assess methodological bias and quality of the studies. Quantitative and qualitative analyses were performed. Heterogeneity was assessed with I2 statistic. Overall, 22 RCTs were included: 12 on prevention (n = 2,471 patients) and 10 in management (n = 797) of DILI/non-acetaminophen DILI-related acute liver failure (ALF). Silymarin (eight studies), bicyclol (four), magnesium isoglycyrrhizinate (three), N-acetylcysteine (three), tiopronin (one), L-carnitine (one), and traditional Chinese medicines (two) were tested in the intervention arm, while control arm mostly received standard supportive care or placebo. Main efficacy criteria in the prevention RCTs was DILI incidence or peak of liver enzymes value. In management RCTs, the efficacy parameter was usually 50 % decrease or normalisation of liver enzymes, or survival rate in DILI-related ALF patients. Overall, 15 trials described the randomisation method, eight were double-blind (n = 672) and nine had sample size estimation (n = 880). Four RCTs involving 377 patients used an intention-to-treat analysis. Based on the scarce number of trials available, tested agents showed limited efficacy in DILI prevention and management and a favourable safety profile. In conclusion, heterogeneity among studies in DILI case qualification and methodologic quality was evident, and the RCTs performed demonstrated limited efficacy of specific interventions. International research networks are needed to establish a framework on RCTs design and therapeutic endpoints.

Acute upper gastrointestinal bleeding: a population-based, five-year follow-up study.

OBJECTIVE: Data on long-term rebleeding risk and mortality in acute upper gastrointestinal bleeding (AUGIB) patients are scarce and comparison to controls are lacking. Aimsof the study were to assess long-term prognosis of AUGIB patients and compare to controls. METHODS: A population-based retrospective case-control study conducted at the National University Hospital of Iceland and included all patients who underwent endoscopy in 2010-2011. AUGIB was defined as haematemesis or coffee ground vomiting leading to hospitalization or occurring in a hospitalized patient. Controls underwent endoscopy in 2010-2011, matched for sex/age. Rebleeding was defined as AUGIB >14 days up to five years after index bleeding. RESULTS: Overall, 303 patients had AUGIB, mean age 67 (±18), controls66 years (±19), females, 51 and 46%, respectively. The five-year rebleeding rate for AUGIB patients was 13% (95%CI 9-17%), higher than the rate of bleeding events in controls, 3% (95%CI 1-5%; log-rank <0.001), hazard ratio (HR) 6.0 (95%CI 2.4-15) when correcting for comorbidities, NSAID's, PPI's and antithrombotics. The mortality of AUGIB patients at end of follow-up was higher when compared to controls, 39% (95%CI 49-33%) vs. 26% (95%CI 30-21%), log-rank <0.001, comorbidity-adjusted HR 1.4 (1.1-1.9). A subanalysis of non-variceal AUGIB yielded similar results in regard to rebleeding and mortality rates. CONCLUSIONS: AUGIB patients were at 6-fold risk of rebleeding compared to bleeding events in controls at five years of follow-up. Five-year mortality was higher in AUGIB patients when compared to controls even when correcting for age and comorbidities, suggesting that an episode of AUGIB indicates serious frailty.

Pharmacokinetics of single and repeated oral doses of esomeprazole and gastrin elevation in healthy males and females.

OBJECTIVE: Gastrin elevation secondary to proton pump inhibitor (PPI) therapy is well documented. Recent studies have demonstrated a sex-related difference where females on PPIs have significantly higher baseline gastrin levels than males. The aim of the study was to analyse the pharmacokinetics of esomeprazole and short-term effect on serum gastrin levels and evaluate potential sex-related difference. MATERIALS AND METHODS: Healthy volunteers received 40 mg of esomeprazole daily for five days. After the 1st and 5th dose blood samples for fasting gastrin and pharmacokinetic analysis were collected at scheduled time-points for eight hours. Esomeprazole was analysed by liquid chromatography and gastrin concentrations were measured using radioimmunoassay. RESULTS: A total of 30 volunteers were enrolled. Females had higher median baseline gastrin (pM) than males 12 (IQR 10-15) vs. 7 (IQR 4-11) (p = .03). In the study cohort, median gastrin levels rose from 10 (IQR 6-14) to 15 (IQR 13-20) (p = .0002). The serum levels for esomeprazole increased by an average of 299.8 ng/mL (p < .001) from day 1 to day 5. Comparison of the esomeprazole pharmacokinetic parameters between males and females revealed no significant sex-related differences. No significant correlation was found between the AUC and the gastrin level on day 5 (p = .15). CONCLUSIONS: In healthy volunteers, serum gastrin increased significantly after a four-day PPI-therapy. There was also a significant increase in serum esomeprazole from day 1 to day 5. The increase in gastrin and esomeprazole concentration was not related to sex and no significant sex-related difference was found in terms of pharmacokinetic parameters. European Clinical Trial Database (2015-002230-41).

Paracetamol poisoning: a population-based study from Iceland.

OBJECTIVE: To examine the incidence and severity of paracetamol poisoning in a population-based cohort in Iceland. A previous study showed a decrease in the incidence during a financial crisis in Iceland, by approximately half (16/100,000 annually). The aims of the study were to assess the incidence and nature of paracetamol poisoning after economic recovery in Iceland and to compare intentional and accidental poisoning. METHODS: Paracetamol serum concentrations were used to identify patients in this retrospective study from 2010-2017. A search was undertaken in laboratory databases for patients with serum paracetamol concentrations, which were grouped by <66 µmol/L (below detection limit) and ≥66 µmol/L. Medical records were reviewed and relevant laboratory and clinical information obtained to determine whether paracetamol poisoning had occurred. RESULTS: Altogether 542 cases of paracetamol poisoning were identified. The mean annual incidence was 27/100,000 (range 22-33). Intentional poisoning was observed in 437/542 (81%) cases, most frequently among females 16-25 years of age. Males ≥65 years were more likely to overdose by accident, which was associated with worse outcomes. Twenty-five (4.6%) patients developed severe paracetamol-induced liver injury and coagulopathy. Overall, six (1.1%) cases were fatal in which paracetamol contributed to the cause of death, with accidental poisoning found in 67% (4/6). CONCLUSIONS: The incidence of paracetamol poisoning has increased in recent years associated with economic recovery in Iceland. Most patients had favourable outcomes. Intentional overdose was most common in young females, whereas accidental overdose was more common in older males and more frequently associated with a fatal outcome.

Acute gastrointestinal bleeding among patients on antiplatelet and anticoagulant therapy after percutaneous coronary intervention.

BACKGROUND: Patients undergoing percutaneous coronary intervention (PCI) require dual antiplatelet therapy and some require additional anticoagulation. We aimed to investigate the incidence of acute gastrointestinal bleeding (AGIB) among PCI patients receiving antiplatelet and anticoagulant therapy. METHODS: A population-based study that included all patients undergoing PCI during 2008-2016 in Iceland. Data from the Icelandic Medicines Registry were obtained on all outpatient prescriptions 1 year after first PCI. Patients receiving single or dual-antiplatelet therapy with or without anticoagulation cotherapy were analyzed. Rehospitalization for AGIB and endoscopic data were obtained within the 12-month follow-up period. RESULTS: A total of 5166 patients (male 75%) underwent PCI during the study period. The incidence of AGIB was 1% (54/5166) per year. The mean age among non-bleeders 65 (±11) years was lower than among bleeders 69 (±9) years (p = .002). The proportion of acute upper GIB (AUGIB) was 56%, whereas lower GIB occurred in 44%. Overall, 41% with AUGIB had PPIs compared to 39% of non-bleeders (NS). The incidence of AGIB among patients on single antiplatelet therapy combined with an anticoagulant was 2.5% compared to 0.9% among those on single antiplatelet treatment alone (p = .028). The number needed to harm (NNH) for treatment with single antiplatelet therapy and anticoagulant therapy compared to single antiplatelet therapy was 62 but no deaths related to AGIB. CONCLUSIONS: The 1-year incidence of AGIB was low with no mortality. Bleeding risk was found to be higher among patients on single antiplatelet therapy combined with anticoagulant therapy compared to patients on single antiplatelet therapy alone.