Browsing by Author "Stolz, Andrew"
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Item Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study(Elsevier, 2017-04) Nicoletti, Paola; Aithal, Guruprasad P.; Bjornsson, Einar S.; Andrade, Raul J.; Sawle, Ashley; Arrese, Marco; Barnhart, Huiman X.; Bondon-Guitton, Emmanuelle; Hayashi, Paul H.; Bessone, Fernando; Carvajal, Alfonso; Cascorbi, Ingolf; Cirulli, Elizabeth T.; Chalasani, Naga; Conforti, Anita; Coulthard, Sally A.; Daly, Mark J.; Day, Christopher P.; Dillon, John F.; Fontana, Robert J.; Grove, Jane I.; Hallberg, Pär; Hernández, Nelia; Ibáñez, Luisa; Kullak-Ublick, Gerd A.; Laitinen, Tarja; Larrey, Dominique; Lucena, M. Isabel; Maitland-van der Zee, Anke H.; Martin, Jennifer H.; Molokhia, Mariam; Pirmohamed, Munir; Powell, Elizabeth E.; Qin, Shengying; Serrano, Jose; Stephens, Camilla; Stolz, Andrew; Wadelius, Mia; Watkins, Paul B.; Floratos, Aris; Shen, Yufeng; Nelson, Matthew R.; Urban, Thomas J.; Daly, Ann K.; International Drug-Induced Liver Injury Consortium; Drug-Induced Liver Injury Network Investigators; International Serious Adverse Events Consortium; Medicine, School of MedicineBACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.Item Clinical and histologic features of azithromycin-induced liver injury(Elsevier, 2015-02) Martinez, Melissa A.; Vuppalanchi, Raj; Fontana, Robert J.; Stolz, Andrew; Kleiner, David E.; Hayashi, Paul H.; Gu, Jiezhun; Hoofnagle, Jay H.; Chalasani, Naga; Department of Medicine, IU School of MedicineBACKGROUND & AIMS: Rare cases of azithromycin-induced hepatotoxicity have been reported, with variable clinical and histologic features. We characterized clinical features and outcomes of azithromycin-induced liver injury. METHODS: We identified patients with azithromycin-induced liver injury from the Drug-Induced Liver Injury Network Prospective Study who had causality scores of definite, highly likely, or probable. Demographic, clinical, and laboratory data and 6-month outcomes were examined. RESULTS: Eighteen patients (72% female; mean age, 37 y) had causality scores of definite (n = 1), highly likely (n = 9), or probable (n = 8). Common presenting symptoms were jaundice, abdominal pain, nausea, and/or pruritus. For 16 patients, abnormal results from liver tests were first detected 14 days after azithromycin cessation (range, 9-20 d). The median duration of azithromycin treatment was 4 days (range, 2-7 d). The pattern of injury was hepatocellular in 10 patients, cholestatic in 6 patients, and mixed in 2 patients. The mean peak level of alanine aminotransferase was 2127 IU/L, of alkaline phosphatase was 481 IU/L, and of total bilirubin was 9.2 mg/dL. Liver histology showed ductopenia and veno-occlusive changes in a few patients. Two individuals had severe hypersensitivity cutaneous reactions. After 6 months, 8 patients had recovered, 4 patients had chronic injury, 1 patient died, and 1 patient underwent liver transplantation (outcomes were unavailable for 4 patients). Two of the patients who died or underwent liver transplantation had underlying chronic liver disease. CONCLUSIONS: Azithromycin-induced liver injury occurs within 1 to 3 weeks after azithromycin initiation and predominantly is hepatocellular in nature. Although most patients recover fully, severe cutaneous reactions, chronic injury, and serious complications leading to death or liver transplantation can occur (ClinicalTrials.gov identifier, NCT00345930).Item Cytokine profiles in acute liver injury-Results from the US Drug-Induced Liver Injury Network (DILIN) and the Acute Liver Failure Study Group(Public Library of Science, 2018-10-25) Bonkovsky, Herbert L.; Barnhart, Huiman X.; Foureau, David M.; Steuerwald, Nury; Lee, William M.; Gu, Jiezhun; Fontana, Robert J.; Hayashi, Paul J.; Chalasani, Naga; Navarro, Victor M.; Odin, Joseph; Stolz, Andrew; Watkins, Paul B.; Serrano, Jose; US Drug-Induced Liver Injury Network; Acute Liver Failure Study Group; Medicine, School of MedicineChanges in levels of cytokines and chemokines have been proposed as possible biomarkers of tissue injury, including liver injury due to drugs. Recently, in acute drug-induced liver injury (DILI), we showed that 19 of 27 immune analytes were differentially expressed and that disparate patterns of immune responses were evident. Lower values of serum albumin (< 2.8 g/dL) and lower levels of only four analytes, namely, IL-9, IL-17, PDGF-bb, and RANTES, were highly predictive of early death [accuracy = 96%]. The goals of this study were to assess levels of the same 27 immune analytes in larger numbers of subjects to learn whether the earlier findings would be confirmed in new and larger cohorts of subjects, compared with a new cohort of healthy controls. We studied 127 subjects with acute DILI enrolled into the US DILIN. We also studied 118 subjects with severe acute liver injury of diverse etiologies, enrolled into the ALF SG registry of subjects. Controls comprised 63 de-identified subjects with no history of liver disease and normal liver tests. Analytes associated with poor outcomes [death before 6 months, n = 32 of the total of 232 non-acetaminophen (Apap) subjects], were lower serum albumin [2.6 vs 3.0 g/dL] and RANTES [6,458 vs 8,999 pg/mL] but higher levels of IL-6 [41 vs 18], IL-8 [78 vs 48], and MELD scores [30 vs 24]. Similar patterns were observed for outcome of death/liver transplant within 6 months. A model that included only serum albumin < 2.8 g/dL and RANTES below its median value of 11,349 had 83% (or 81%) accuracy for predicting early death (or early death/liver transplant) in 127 subjects from DILIN. No patterns of serum immune analytes were reflective of the etiologies of acute liver failure, but there were cytokine patterns that predicted prognosis in both acute DILI and ALF.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 HLA-B*35:01 and Green Tea Induced Liver Injury(Wiley, 2021-06) Hoofnagle, Jay H.; Bonkovsky, Herbert L.; Phillips, Elizabeth J.; Li, Yi-Ju; Ahmad, Jawad; Barnhart, Huiman; Durazo, Francisco; Fontana, Robert J.; Gu, Jiezhun; Khan, Ikhlas; Kleiner, David E.; Koh, Christopher; Rockey, Don C.; Seeff, Leonard B.; Serrano, Jose; Stolz, Andrew; Tillmann, Hans L.; Vuppalanchi, Raj; Navarro, Victor J.; Medicine, School of MedicineBackground and aims: Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. Approach and results: Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). Conclusions: Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.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 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(Elsevier, 2023) Nicoletti, Paola; Dellinger, Andrew; Li, Yi Ju; Barnhart, Huiman X.; Chalasani, Naga; Fontana, Robert J.; Odin, Joseph A.; Serrano, Jose; Stolz, Andrew; Etheridge, Amy S.; Innocenti, Federico; Govaere, Olivier; Grove, Jane I.; Stephens, Camilla; Aithal, Guruprasad P.; Andrade, Raul J.; Bjornsson, Einar S.; Daly, Ann K.; Lucena, M. Isabel; Watkins, Paul B.; Drug-Induced Liver Injury Network (DILIN); International Drug-Induced Liver Injury Consortium (iDILIC); Prospective European Drug-Induced Liver Injury (Pro-Euro DILI) Investigators; Medicine, School of MedicineBackground & 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.Item Idiosyncratic drug induced liver injury in African-Americans is associated with greater morbidity and mortality compared to Caucasians(Nature Publishing group, 2017-09) Chalasani, Naga; Reddy, K. Rajender K.; Fontana, Robert J.; Barnhart, Huiman; Gu, Jiezhun; Hayashi, Paul H.; Ahmad, Jawad; Stolz, Andrew; Navarro, Victor; Hoofnagle, Jay H.; Medicine, School of MedicineBackground Idiosyncratic drug induced liver injury (DILI) is a rare but potentially serious liver disorder and a major cause of significant liver injury. Limited data exist on racial differences in DILI incidence, presentation and course. Aim & Methods We compared the causative agents, clinical features and outcomes of DILI among self-described African-Americans and non-Hispanic whites (Caucasians) enrolled in the DILIN Prospective Study. Individuals with definite, highly likely, or probable DILI enrolled between Sept 2004 and Feb 2016 were included in this analysis. Results 144 African-Americans and 841 Caucasian patients met the eligibility criteria. Causal medications varied by race: trimethoprim/sulfamethoxazole being the most common cause among African-Americans (7.6% vs 3.6%) followed by methyldopa (4% vs <1%), phenytoin (5% vs <1%), isoniazid (4% vs 4%) and amoxicillin/clavulanate (4.1% vs 13.4%). The severity of illness, however, tended to be greater in African-Americans than Caucasians as determined by peak mean bilirubin (14.3 vs 12.8 mg/dL), INR (1.9 vs 1.6) and DILIN severity score (3.0 vs 2.6). The frequency of severe cutaneous reactions was significantly higher in African-Americans (2.1 vs. 0.36% in Caucasians, p=0.048). African-Americans also had higher rates of hospitalization (76.7% vs 57.6%, p<0.001), liver transplantation or liver related death by 6 months (10.2% vs 5.8%, p=0.02 after controlling for selected covariates) and chronic DILI (24% vs. 16%, p=0.06). Conclusions The most common DILI causative agents differ between African-Americans and Caucasians. African-Americans are more likely to have severe cutaneous reactions and more severe liver injury leading to worse outcomes, including death and liver transplant. [Word Count 250]Item Importance of Hepatitis C Virus RNA Testing in Patients with Suspected Drug-Induced Liver Injury(Springer, 2019-03-29) Ahmad, Jawad; Reddy, K. Rajender; Tillmann, Hans L.; Hayashi, Paul H.; Chalasani, Naga; Fontana, Robert J.; Navarro, Victor J.; Stolz, Andrew; Barnhart, Huiman; Cloherty, Gavin A.; Hoofnagle, Jay H.; Medicine, School of MedicineBackground & Aims: The aims were to review the diagnosis, testing and presentation of acute hepatitis C (HCV) in patients initially diagnosed to have drug-induced liver injury (DILI) enrolled in the US DILI Network. Methods: All patients with suspected DILI underwent testing for competing causes of liver injury and returned for 6-month follow-up. Causality was adjudicated by consensus expert opinion. Results: Between 2004–2016, 1518 patients were enrolled and adjudicated and underwent 6 months of follow up. Initial locally acquired anti-HCV results were available in 1457 (96%), but HCV RNA in only 795 (52%). Stored sera were available for repeat testing, so that results were available on all 1518 patients (1457 for anti-HCV and 1482 for HCV RNA). 104 subjects (6.9%) had evidence of HCV infection- 10 positive for HCV RNA alone, 16 for anti-HCV alone and 78 for both. All 104 HCV-positive cases were reviewed and 23 cases were adjudicated as acute HCV. All presented with acute hepatocellular injury with median ALT 1448 U/L, alkaline phosphatase 232 U/L and total bilirubin 10.8 mg/dL. 22 (96%) patients were jaundiced. While all 23 cases initially had been suspected of having DILI, 19 were adjudicated as acute HCV and not DILI at the 6 month follow-up; while 4 were still considered DILI. Conclusions: 23 of 1518 (1.5%) cases of suspected DILI were due to acute HCV infection. We recommend that initial and follow up HCV RNA testing should be performed to exclude HCV in patients with acute hepatocellular injury and suspected DILI.Item Liver Injury Associated with Turmeric-A Growing Problem: Ten Cases from the Drug-Induced Liver Injury Network [DILIN](Elsevier, 2023) Halegoua-DeMarzio, Dina; Navarro, Victor; Ahmad, Jawad; Avula, Bharathi; Barnhart, Huiman; Barritt, A. Sidney; Bonkovsky, Herbet L.; Fontana, Robert J.; Ghabril, Marwan S.; Hoofnagle, Jay H.; Khan, Ikhlas A.; Kleiner, David E.; Phillips, Elizabeth; Stolz, Andrew; Vuppalanchi, Raj; Medicine, School of MedicineBackground: Turmeric is a commonly used herbal product that has been implicated in causing liver injury. The aim of this case series is to describe the clinical, histologic, and human leukocyte antigen (HLA) associations of turmeric-associated liver injury cases enrolled the in US Drug-Induced Liver Injury Network (DILIN). Methods: All adjudicated cases enrolled in DILIN between 2004 and 2022 in which turmeric was an implicated product were reviewed. Causality was assessed using a 5-point expert opinion score. Available products were analyzed for the presence of turmeric using ultra-high-performance liquid chromatography. Genetic analyses included HLA sequencing. Results: Ten cases of turmeric-associated liver injury were found, all enrolled since 2011, and 6 since 2017. Of the 10 cases, 8 were women, 9 were White, and median age was 56 years (range 35-71). Liver injury was hepatocellular in 9 patients and mixed in 1. Liver biopsies in 4 patients showed acute hepatitis or mixed cholestatic-hepatic injury with eosinophils. Five patients were hospitalized, and 1 patient died of acute liver failure. Chemical analysis confirmed the presence of turmeric in all 7 products tested; 3 also contained piperine (black pepper). HLA typing demonstrated that 7 patients carried HLA-B*35:01, 2 of whom were homozygous, yielding an allele frequency of 0.450 compared with population controls of 0.056-0.069. Conclusion: Liver injury due to turmeric appears to be increasing in the United States, perhaps reflecting usage patterns or increased combination with black pepper. Turmeric causes potentially severe liver injury that is typically hepatocellular, with a latency of 1 to 4 months and strong linkage to HLA-B*35:01.