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Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.

ABSTRACT: Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled.Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months. Patients with acetaminophen liver injury were excluded.DILI was caused by a single prescription medication in 73% of the cases, by dietary supplements in 9%, and by multiple agents in 18%. More than 100 different agents were associated with DILI; antimicrobials (45.5%) and central nervous system agents (15%) were the most common. Causality was considered to be definite in 32%, highly likely in 41%, probable in 14%, possible in 10%, and unlikely in 3%. Acute hepatitis C virus (HCV) infection was the final diagnosis in 4 of 9 unlikely cases. Six months after enrollment, 14% of patients had persistent laboratory abnormalities and 8% had died; the cause of death was liver related in 44%.DILI is caused by a wide array of medications, herbal supplements, and dietary supplements. Antibiotics are the single largest class of agents that cause DILI. Acute HCV infection should be excluded in patients with suspected DILI by HCV RNA testing. The overall 6-month mortality was 8%, but the majority of deaths were not liver related.

SUBMITTER: Chalasani N

PROVIDER: S-EPMC3654244 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.

Chalasani Naga N Fontana Robert J RJ Bonkovsky Herbert L HL Watkins Paul B PB Davern Timothy T Serrano Jose J Yang Hongqiu H Rochon James J

Gastroenterology 20080917 6

<h4>Background & aims</h4>Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled.<h4>Methods</h4>Patients with suspected DILI were enrolled based ...[more]

PMID: 18955056

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Project description:Background & aimsThe Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study.MethodsIn an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI.ResultsAmong 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation, and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P = .09) and mortality was significantly higher (16% vs 5.2%; P < .001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared with those without liver disease (6.7% vs 1.5%; P = .006). Forty-one cases with latency ≤7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared with individuals younger than 65 years, individuals 65 years or older (n = 149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died.ConclusionsMortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

Project description:Background & aimsNitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN).MethodsSeventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004-2020. HLA alleles were compared between NTF-DILI and three control groups: population (n = 14,001), idiopathic autoimmune hepatitis (n = 231), and non-NTF DILI (n = 661).ResultsLiver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p = 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p = 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p = 1.15 × 10-4), idiopathic autoimmune hepatitis (OR 11.77, p = 7.76 × 10-5), and non-NTF DILI (OR 3.34, p = 0.003).ConclusionNTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04. To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies.Impact and implicationsNitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin.

Project description:BACKGROUND:Acute kidney injury (AKI) during pregnancy is a public health problem and is associated with maternal and fetal morbidity and mortality. Clinical outcomes and health care utilization in pregnancy-related AKI, especially in women with diabetes, are not well studied. METHODS:Using data from the 2006 to 2015 Nationwide Inpatient Sample, we identified 42,190,790 pregnancy-related hospitalizations in women aged 15-49 years. We determined factors associated with AKI, including race/ethnicity, and associations between AKI and inpatient mortality, and between AKI and cardiovascular (CV) events, during pregnancy-related hospitalizations. We calculated health care expenditures from pregnancy-related AKI hospitalizations. RESULTS:Overall, the rate of AKI during pregnancy-related hospitalizations was 0.08%. In the adjusted regression analysis, a higher likelihood of AKI during pregnancy-related hospitalizations was seen in 2015 (OR 2.20; 95% CI 1.89-2.55) than in 2006; in older women aged 36-40 years (OR 1.49; 95% CI 1.36-1.64) and 41-49 years (OR 2.12; 95% CI 1.84-2.45) than in women aged 20-25 years; in blacks (OR 1.52; 95% CI 1.40-1.65) and Native Americans (OR 1.45; 95% CI 1.10-1.91) than in whites, and in diabetic women (OR 4.43; 95% CI 4.04-4.86) than in those without diabetes. Pregnancy-related hospitalizations with AKI were associated with a higher likelihood of inpatient mortality (OR 13.50; 95% CI 10.47-17.42) and CV events (OR 9.74; 95% CI 9.08-10.46) than were hospitalizations with no AKI. The median cost was higher for a delivery hospitalization with AKI than without AKI (USD 18,072 vs. 4,447). CONCLUSION:The rates of pregnancy-related AKI hospitalizations have increased during the last decade. Factors associated with a higher likelihood of AKI during pregnancy included older age, black and Native American race/ethnicity, and diabetes. Hospitalizations with pregnancy-related AKI have an increased risk of inpatient mortality and CV events, and a higher health care utilization than do those without AKI.

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Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.

Publications

Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.

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