Browsing by Subject "Hepatotoxicity"
Now showing 1 - 10 of 14
Results Per Page
Sort Options
Item A state-of-the-art update on hepatotoxicity: Introduction to the special series on drug-induced liver injury(Wolters Kluwer, 2024-07-03) Dara, Lily; Ghabril, Marwan; Medicine, School of MedicineItem Articles You May Have Missed(Springer Verlag, 2018-12) Nanagas, Kristine; Avera, Robert; Purpura, Andrea; Murphy, Jillian; Kao, Louise; Emergency Medicine, School of MedicineItem Characteristics of Idiosyncratic Drug-induced Liver Injury in Children: Results From the DILIN Prospective Study(Wiley, 2011) Molleston, Jean P.; Fontana, Robert J.; Lopez, M. James; Kleiner, David E.; Gu, Jiezhun; Chalasani, Naga; Drug-Induced Liver Injury Network; Pediatrics, School of MedicineBackground: The spectrum and severity of idiosyncratic drug-induced liver injury (DILI) in children are not well established. Patients and methods: The DILIN (Drug-Induced Liver Injury Network) Prospective Study is a longitudinal multicenter study designed to determine the etiologies, risk factors, and outcomes of suspected DILI. Between September 2004 and September 2009, 30 children ages 2 to 18 years with suspected DILI who met eligibility criteria were enrolled and studied for at least 6 months. Results: Mean age was 14 years; 70% were girls. Antimicrobial (50%) and central nervous system agents (40%) were the most commonly implicated drug classes, with minocycline (4), isoniazid (3), azithromycin (3), atomoxetine (3), and lamotrigine (3) the leading agents. Median time from drug initiation to symptom onset was 32 days. Peak (median) liver chemistries were aspartate aminotransferase 503 U/L, alanine aminotransferase 727 U/L, alkaline phosphatase 331 U/L, and total bilirubin 3.9 mg/dL. Autoantibodies were common (64%). Liver injury pattern was hepatocellular 78%, cholestatic 13%, and mixed 9%. The DILI episode was scored: mild 32%, moderate 44%, severe 20%, and fatal (within 6 months) 4%. Causality assessment was definite 36%, very likely 36%, probable 16%, possible 8%, and unlikely 4%. Seven percent had persistent liver test abnormalities at 6-month follow-up suggesting chronic DILI. Liver biopsies from 12 children most frequently demonstrated chronic hepatitis or bile duct injury. Conclusions: Idiosyncratic DILI in children is most commonly caused by antimicrobial or central nervous system agents and usually presents with a hepatocellular injury pattern. The majority of patients recover, but morbidity and infrequent mortality are seen.Item Clinical characteristics of antiepileptic-induced liver injury in patients from the DILIN prospective study(Elsevier, 2022) Chalasani, Naga; Bonkovsky, Herbert L.; Stine, Jonathan G.; Gu, Jiezhun; Barnhart, Huiman; Jacobsen, Elin; Björnsson, Einar; Fontana, Robert J.; Kleiner, David E.; Hoofnagle, Jay H.; Drug-Induced Liver Injury Network (DILIN) Study Investigators; Medicine, School of MedicineBackground & aims: Antiepileptic drugs (AEDs) are a common cause of drug-induced liver injury (DILI). Over the last few decades, several newer AEDs were approved for marketing in the United States, and they are increasingly prescribed for indications other than seizures. Contemporaneous data related to trends and characteristics of AED-related liver injury are sparse. Methods: We report the trends, characteristics, and outcomes of patients with AED-related DILI enrolled into the DILIN Prospective Study between 2004 and 2020. Results: Among 1,711 participants with definite, highly likely, or probable DILI, 66 (3.9%) had AED-related DILI (lamotrigine [n = 18], phenytoin [n = 16], carbamazepine [n = 11], valproate [n = 10], gabapentin [n = 4], and others [n = 7]). The frequency of AED-related liver injury significantly decreased during the study period (from 8.5% of cases during 2004-2007 to 2.6% during 2015-2020, p = 0.01). AEDs other than phenytoin were commonly prescribed for non-seizure indications. Compared to non-AEDs, patients with AED-related liver injury were younger (mean age 38.5 vs. 50.1 years-old, p <0.001) and more likely African American (27% vs. 12%, p = 0.008). DRESS was common with liver injury caused by lamotrigine, phenytoin, and carbamazepine, but not valproate or gabapentin. Liver injury severity was moderate to severe in the majority: 5 died, and 3 underwent orthotopic liver transplantation (OLT). No patient with lamotrigine-related DILI, including 13 with hepatocellular jaundice, died or needed OLT, while 3 out of 16 patients (19%) with phenytoin-related DILI either died or required OLT. Conclusion: The frequency of AED-related liver injury significantly decreased over the last 2 decades in our experience. AED-related liver injury has several distinctive features, including a preponderance in African American patients and those with immunoallergic skin reactions, with outcomes depending on the type of AED involved. Lay summary: Medications used to treat epilepsy may sometimes cause severe liver injury. However, several new medications have been approved over the last 2 decades and they may not be as toxic to the liver as older antiepileptic medications (AEDs). This study shows that overall liver injury due to AEDs is decreasing, likely due to decreasing use of older AEDs. Liver injury due to AEDs appears to be more common in African Americans and is commonly associated with allergic skin reactions.Item Drug Induced Liver Injury Caused by Intravenously Administered Medications: The Drug Induced Liver Injury Network (DILIN) Experience(Wolters Kluwer, 2013) Ghabril, Marwan; Fontana, Robert; Rockey, Don; Jiezhun, Gu; Chalasani, Naga; Medicine, School of MedicineBackground and aims: Idiosyncratic drug-induced liver injury (DILI) can be caused by intravenous (IV) medications, but the characteristics of DILI caused by these agents are not known. The aim of this study is to characterize the clinical features of subjects with suspected DILI associated with IV agents enrolled into the Drug Induced Liver Injury Network Prospective Study. Methods: Subjects with suspected DILI due to IV medications with probable, highly likely, or definite casuality scores were eligible. Results: Between 2004 and October 2010, 542 cases of DILI were adjudicated for causality, of which 32 were eligible for inclusion in this study. DILI was ascribed to a single IV agent in 27 subjects, and to multiple IV agents in 5 subjects. Antimicrobial agents (62%), antineoplastic agents (16%), and phenytoin (9%) were most commonly implicated. The pattern of liver injury was hepatocellular in 30%, mixed in 33%, and cholestatic in 37%. The peak alanine aminotransferase (ALT), alkaline phosphatase (AlkP), and total bilirubin were 686 ± 915 U/L, 623 ± 563 U/L, and 8.7 ± 10.3 mg/dL, respectively. The duration for ≥ 50% improvement from peak ALT, AlkP, and total bilirubin were 25 ± 37, 59 ± 69, and 20 ± 28 days, respectively. DILI severity was mild in 37%, moderate in 47%, severe in 13%, and fatal in 3%, with no liver transplantation. Their causality was adjudicated as definite in 5, very likely in 17, and probable in 10 subjects. The frequency of chronic DILI was 13%. Conclusions: Antimicrobial and antineoplastic agents are the most common IV agents to cause DILI. DILI ascribed to IV agents is relatively infrequent, but its outcomes are similar to those of the overall Drug Induced Liver Injury Network cohort.Item Drug-Induced Liver Injury due to Medications for Alcohol Use Disorder: Results from the DILIN Prospective Study(Wolters Kluwer, 2025) Gopalakrishna, Harish; Ghabril, Marwan; Gu, Jiezhun; Li, Yi Ju; Fontana, Robert J.; Kleiner, David E.; Koh, Christopher; Chalasani, Naga; Drug-Induced Liver Injury Network; Medicine, School of MedicineObjectives: Concerns about drug-induced liver injury (DILI) may deter physicians from prescribing medications for alcohol use disorder (MAUD). We aim to explore DILI due to MAUD in Drug-Induced Liver Injury Network (DILIN) prospective study. Methods: High-confidence DILI cases (ie, definite, highly likely, or probable) due to MAUD in DILIN prospective study (2004-2024) were included. Demographic, clinical, laboratory data, and 6-month outcomes were analyzed. HLA allele frequency (AF) of disulfiram cases was compared to matched controls with DILI due to non-MAUD (DILI controls). Results: Among 1975 high-confidence cases, 13 were attributed to MAUD (11 disulfiram; 1 naltrexone and 1 baclofen; and none from acamprosate). Median age was 45 years, with 77% female and 85% White. All had hepatocellular injury. In disulfiram group, the median time for DILI occurrence was 34 days. Eight patients developed jaundice, with 3 fatal or near-fatal cases (2 liver transplantation and 1 liver-related death). Five (71%) patients with severe or fatal disulfiram DILI had underlying liver disease. AF for HLA-C*01:02 (OR, 6.29; P = 0.02) and DRB1*09:01 (OR, 10.16; P = 0.02) were significantly higher in disulfiram cases than in DILI controls. DILI from baclofen and naltrexone was mild and self-limited with no chronic DILI. Conclusions: Disulfiram is the leading cause of DILI among MAUD and is most common in women. Disulfiram can cause severe DILI and is associated with HLA-C*01:02 and DRB1*09:01. Baclofen and naltrexone can cause mild to moderate self-limited DILI. There were no cases of acamprosate. These findings suggest DILI due to MAUD are less frequent.Item Features of Autoimmune Hepatitis in Patients With Drug-induced Liver Injury(Elsevier, 2017-01) de Boer, Ynto S.; Kosinski, Andrzej S.; Urban, Thomas J.; Zhao, Zhen; Long, Nanye; Chalasani, Naga; Kleiner, David E.; Hoofnagle, Jay H.; Drug-Induced Liver Injury Network.; Medicine, School of MedicineBACKGROUND & AIMS: Drug-induced liver injury (DILI) has features similar to those of other liver diseases including autoimmune hepatitis (AIH). We aimed to characterize the clinical and autoimmune features of liver injury caused by nitrofurantoin, minocycline, methyldopa, or hydralazine. METHODS: We analyzed data from 88 cases of DILI attributed to nitrofurantoin, minocycline, methyldopa, or hydralazine included in the Drug-Induced Liver Injury Network prospective study from 2004 through 2014. Sera were collected from patients at baseline and follow-up examination and tested for levels of immunoglobulin G (IgG), antibodies to nuclear antigen (ANA), smooth muscle (SMA), and soluble liver antigen (SLA). An autoimmune score was derived on the basis of increases in levels of IgG, ANA, SMA, and SLA (assigned values of 0, 1+, or 2+). AIH-associated HLA-DRB1*03:01 and HLA-DRB1*04:01 allele frequencies were compared with those of the general population (controls). RESULTS: Of the 88 cases, 80 were women (91%), 74% had hepatocellular injury, and 25% had severe injury. At the onset of DILI, 39% of cases had increased levels of IgG, 72% had increased levels of ANA, 60% had increased levels of SMA, and none had increases in SLA. A phenotype of autoimmunity (autoimmune score ≥2) was observed in 82% of cases attributed to nitrofurantoin and 73% of cases attributed to minocycline (73%) but only 55% of cases attributed to methyldopa and 43% of cases attributed to hydralazine (P = .16 for nitrofurantoin and minocycline vs methyldopa and hydralazine). We observed a decrease in numbers of serum samples positive for ANA (P = .01) or SMA (P < .001) and in autoimmune scores (P < .001) between DILI onset and follow-up. Similar percentages of patients with DILI had HLA-DRB1*03:01 (15%) and HLA-DRB1*04:01 (9%) as controls (12% and 9%, respectively). CONCLUSIONS: In analysis of data from the DILIN prospective study, we found that most cases of DILI attributed to nitrofurantoin or minocycline and about half of cases that were due to methyldopa and hydralazine have a phenotype of autoimmunity similar to AIH. These features decrease with recovery of the injury and are not associated with the typical HLA alleles found in patients with idiopathic AIH.Item Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury(Elsevier, 2021) Vuppalanchi, Raj; Bonkovsky, Herbert L.; Ahmad, Jawad; Barnhart, Huiman; Durazo, Francisco; Fontana, Robert J.; Gu, Jiezhun; Khan, Ikhlas; Kleiner, David E.; Koh, Christopher; Rockey, Don C.; Phillips, Elizabeth J.; Li, Yi-Ju; Serrano, Jose; Stolz, Andrew; Tillmann, Hans L.; Seeff, Leonard B.; Hoofnagle, Jay H.; Navarro, Victor J.; Medicine, School of MedicineBackground & Aims Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G cambogia have been reported, but its role in liver injury is controversial. Methods Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G cambogia either alone (n = 5) or in combination with green tea (n = 16) or Ashwagandha (n = 1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G cambogia and 103 patients from other HDS. Results Patients who took G cambogia were between 17 and 54 years, with liver injury arising 13–223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G cambogia group (P < .018), the median time for improvement in total bilirubin was significantly lower compared with the control groups (10 vs 17 and 13 days; P = .03). The presence of HLA-B∗35:01 allele was significantly higher in the G cambogia containing HDS (55%) compared with patients because of other HDS (19%) (P = .002) and those with acute liver injury from conventional drugs (12%) (P = 2.55 × 10–6). Conclusions The liver injury caused by G cambogia and green tea is clinically indistinguishable. The possible association with HLA-B∗35:01 allele suggests an immune-mediated mechanism of injury. Clinical Trials.gov number: NCT00345930.Item Human Leukocyte Antigen B*14:01 and B*35:01 Are Associated With Trimethoprim-Sulfamethoxazole Induced Liver Injury(Wolters Kluwer, 2021) Li, Yi-Ju; Phillips, Elizabeth J.; Dellinger, Andrew; Nicoletti, Paola; Schutte, Ryan; Li, Danmeng; Ostrov, David A.; Fontana, Robert J.; Watkins, Paul B.; Stolz, Andrew; Daly, Ann K.; Aithal, Guruprasad P.; Barnhart, Huiman; Chalasani, Naga; Drug-induced Liver Injury Network (DILIN); Medicine, School of MedicineBackground and aims: Trimethoprim (TMP)-sulfamethoxazole (SMX) is an important cause of idiosyncratic drug-induced liver injury (DILI), but its genetic risk factors are not well understood. This study investigated the relationship between variants in the human leukocyte antigen (HLA) class 1 and 2 genes and well-characterized cases of TMP-SMX DILI. Approach and results: European American and African American persons with TMP-SMX DILI were compared with respective population controls. HLA sequencing was performed by Illumina MiSeq (Illumina, San Diego, CA) for cases. The HLA genotype imputation with attribute bagging program was used to impute HLA alleles for controls. The allele frequency difference between case patients and controls was tested by Fisher's exact tests for each ethnic group. For European Americans, multivariable logistic regression with Firth penalization was used to test the HLA allelic effect after adjusting for age and the top two principal components. Molecular docking was performed to assess HLA binding with TMP and SMX. The European American subset had 51 case patients and 12,156 controls, whereas the African American subset had 10 case patients and 5,439 controls. Four HLA alleles were significantly associated in the European American subset, with HLA-B*14:01 ranking at the top (odds ratio, 9.20; 95% confidence interval, 3.16, 22.35; P = 0.0003) after covariate adjustment. All carriers of HLA-B*14:01 with TMP-SMX DILI possessed HLA-C*08:02, another significant allele (P = 0.0026). This pattern was supported by HLA-B*14:01-HLA-C*08:02 haplotype association (P = 1.33 × 10-5 ). For the African American patients, HLA-B*35:01 had 2.8-fold higher frequency in case patients than in controls, with 5 of 10 patients carrying this allele. Molecular docking showed cysteine at position 67 in HLA-B*14:01 and phenylalanine at position 67 in HLA-B*35:01 to be the predictive binding sites for SMX metabolites. Conclusions: HLA-B*14:01 is associated with TMP-SMX DILI in European Americans, and HLA-B*35:01 may be a potential genetic risk factor for African Americans.Item Liver Injury Associated with Kratom, A Popular Opioid-Like Product: Experience from the U.S. Drug Induced liver Injury Network(Elsevier, 2021) Ahmad, Jawad; Odin, Joseph A.; Hayashi, Paul H.; Fontana, Robert J.; Conjeevaram, Hari; Avula, Bharathi; Khan, Ikhlas A.; Barnhart, Huiman; Vuppalanchi, Raj; Navarro, Victor J.; Drug-Induced Liver Injury Network; Medicine, School of MedicineBackground: Kratom is a botanical product used as an opium substitute with abuse potential. Methods: Assessment of suspected cases of kratom-induced liver injury in a prospective US cohort. Results: Eleven cases of liver injury attributed to kratom were identified with a recent increase. The majority were male with median age 40 years. All were symptomatic and developed jaundice with a median latency of 14 days. The liver injury pattern was variable, most required hospitalization and all eventually recovered. Biochemical analysis revealed active kratom ingredients. Conclusion: Kratom can cause severe liver injury with jaundice.