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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 Death and Liver Transplantation within Two Years of Onset of Drug-Induced Liver Injury(Wiley, 2017) Hayashi, Paul H.; Rockey, Don; Fontana, Robert J.; Tillmann, Hans L.; Kaplowitz, Neil; Barnhart, Huiman; Gu, Jiezhan; Chalasani, Naga; Reddy, K. Rajender; Sherker, Averell H.; Hoofnagle, Jay H.; Department of Medicine, IU School of MedicineDrug-induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities ispoorly characterized particularly when fatalities occur > 26 weeks after DILI onset. We analyzed patients in the U.S. Drug-Induced Liver Injury Network prospective study having a fatal outcome within 2 years of onset. Each case was reviewed by 8 Network investigators and categorized as DILI having a primary, contributory or no role in the fatality. We subcategorized primary role cases as acute, chronic, acute-on-chronic or acute cholestatic liver failure. For contributory and no role cases, we assigned a primary cause of death. Among 1089 patients, 107 (9.8%) fatalities occurred within 2 years. DILI had a primary role in 68 (64%), a contributory role in 15 (14%) and no role in 22 (21%); 2 had insufficient data. Among primary role cases, 74% had acute, 13% chronic, 7% acute-on-chronic and 6% acute cholestatic failure. For the 15 contributory role cases, common causes of death included sepsis, malignancy and severe cutaneous reactions with multi-organ failure. For the 22 no role cases, malignancies accounted for most fatalities. Higher bilirubin, coagulopathy, leukocytosis and thrombocytopenia were independently associated with DILI fatalities. nR Hy's Law had a higher positive predictive value for overall fatality (14% vs. 10%) and stronger independent association with DILI fatalities within 26 weeks compared to the original version of Hy's Law (HR: 6.2, CI 3.4 – 11.1 vs. 2.2, CI 1.3-3.7). DILI leads directly or indirectly to fatality in 7.6% of cases; 40% of these have non-acute liver failure courses. nR Hy's Law better identifies risk for death compared to the original Hy's Law.Item Declining liver graft quality threatens the future of liver transplantation in the United States(Wiley, 2015-08) Orman, Eric S.; Mayorga, Maria E.; Wheeler, Stephanie B.; Townsley, Rachel M.; Toro-Diaz, Hector H.; Hayashi, Paul H.; Barritt IV, Sidney A; Department of Medicine, IU School of MedicineNational liver transplantation (LT) volume has declined since 2006, in part because of worsening donor organ quality. Trends that degrade organ quality are expected to continue over the next 2 decades. We used the United Network for Organ Sharing (UNOS) database to inform a 20-year discrete event simulation estimating LT volume from 2010 to 2030. Data to inform the model were obtained from deceased organ donors between 2000 and 2009. If donor liver utilization practices remain constant, utilization will fall from 78% to 44% by 2030, resulting in 2230 fewer LTs. If transplant centers increase their risk tolerance for marginal grafts, utilization would decrease to 48%. The institution of "opt-out" organ donation policies to increase the donor pool would still result in 1380 to 1866 fewer transplants. Ex vivo perfusion techniques that increase the use of marginal donor livers may stabilize LT volume. Otherwise, the number of LTs in the United States will decrease substantially over the next 15 years. In conclusion, the transplant community will need to accept inferior grafts and potentially worse posttransplant outcomes and/or develop new strategies for increasing organ donation and utilization in order to maintain the number of LTs at the current level.Item Development and Validation of Model Consisting of Comorbidity Burden to Calculate Risk of Death Within 6 months for Patients With Suspected Drug-Induced Liver Injury(Elsevier, 2019-11) Ghabril, Marwan; Gu, Jiezhun; Yoder, Lindsay; Corbito, Laura; Ringel, Amit; Beyer, Christian D.; Vuppalanchi, Raj; Barnhart, Huiman; Hayashi, Paul H.; Chalasani, Naga; Medicine, School of MedicineBackground & Aims: Patients with drug-induced liver injury (DILI) frequently have comorbid conditions, but the effects of non-liver comorbidities on outcome is not well understood. We investigated the association between co-morbidity burden and outcomes of patients with DILI, and developed and validated a model to calculate risk of death within 6 months. Methods: A multiple logistic regression model identified variables independently associated with death within 6 months of presenting with suspected DILI (6-month mortality) for 306 patients enrolled in the DILIN prospective study at Indiana University (discovery cohort). The model was validated using data from 247 patients with suspected DILI enrolled in the same study at the University of North Carolina (validation cohort). Medical comorbidity burden was calculated using the Charlson comorbidity index—patients with scores higher than 2 were considered to have significant comorbidities. Results: Six-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. In the discovery cohort, significant comorbidities (odds ratio [OR], 5.4; 95% CI 2.1 – 13.8), model for end-stage liver disease score (OR, 1.11; 95% CI, 1.04–1.17), and serum level of albumin at presentation (OR, 0.39; 95% CI, 0.2–0.76) were independently associated with 6-month mortality. A model based on these 3 variables identified patients who died within 6 months with c-statistic values of 0.89 (95% CI, 0.86–0.94) in the discovery cohort and 0.91 (95% CI, 0.83–0.99) in the validation cohort. We developed a web-based calculator to determine risk of death within 6 months for patients with suspected DILI for use in the clinic. Conclusions: We developed and validated a model based on comorbidity burden, model for end-stage liver disease score, and serum level of albumin that predicts 6-month mortality in patients with suspected DILI.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 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.Item Liver Injury due to Ashwagandha. A Case Series from Iceland and the U.S. Drug-Induced Liver Injury Network(Wiley, 2020-04) Björnsson, Helgi K.; Björnsson, Einar S.; Avula, Bharathi; Khan, Ikhlas A.; Jonasson, Jon G.; Ghabril, Marwan; Hayashi, Paul H.; Navarro, Victor; Medicine, School of MedicineBackground & aims: Ashwagandha (Withania somnifera) is widely used in Indian Ayurvedic medicine. Several dietary supplements containing ashwagandha are marketed in the US and Europe, but only one case of drug-induced liver injury (DILI) due to ashwagandha has been published. The aim of this case series was to describe the clinical phenotype of suspected ashwagandha-induced liver injury. Methods: Five cases of liver injury attributed to ashwagandha-containing supplements were identified; three were collected in Iceland during 2017-2018 and two from the Drug-Induced Liver Injury Network (DILIN) in 2016. Other causes for liver injury were excluded. Causality was assessed using the DILIN structured expert opinion causality approach. Results: Among the five patients, three were males; mean age was 43 years (range 21-62). All patients developed jaundice and symptoms such as nausea, lethargy, pruritus and abdominal discomfort after a latency of 2-12 weeks. Liver injury was cholestatic or mixed (R ratios 1.4-3.3). Pruritus and hyperbilirubinaemia were prolonged (5-20 weeks). No patient developed hepatic failure. Liver tests normalized within 1-5 months in four patients. One patient was lost to follow-up. One biopsy was performed, showing acute cholestatic hepatitis. Chemical analysis confirmed ashwagandha in available supplements; no other toxic compounds were identified. No patient was taking potentially hepatotoxic prescription medications, although four were consuming additional supplements, and in one case, rhodiola was a possible causative agent along with ashwagandha. Conclusions: These cases illustrate the hepatotoxic potential of ashwagandha. Liver injury is typically cholestatic or mixed with severe jaundice and pruritus, but self-limited with liver tests normalizing in 1-5 months.Item Paracentesis is Associated with Reduced Mortality in Patients Hospitalized with Cirrhosis and Ascites(Elsevier B.V., 2014-03) Orman, Eric S.; Hayashi, Paul H.; Bataller, Ramon; Barritt, A. Sidney IV; Department of Medicine, IU School of MedicineDiagnostic paracentesis is recommended for patients with cirrhosis admitted to the hospital for ascites or encephalopathy. However, it is not known if clinicians in the United States adhere to this recommendation; a relationship between paracentesis and clinical outcome has not been reported. We analyzed a US database to determine the frequency of paracentesis and its association with mortality. Methods The 2009 Nationwide Inpatient Sample (which contains data from approximately 8 million hospital discharges each year) was used to identify patients with cirrhosis and ascites admitted with a primary diagnosis of ascites or encephalopathy. In-hospital mortality, length of stay, and hospital charges were compared for those who did and did not undergo paracentesis. Outcomes were compared for those who received an early paracentesis (within 1 day of admission) and those who received one later. Results Of 17,711 eligible admissions, only 61% underwent paracentesis. In-hospital mortality was reduced by 24% among patients who underwent paracentesis (6.5% vs 8.5%, adjusted odds ratio [OR], 0.55; 95% confidence interval [CI], 0.41–0.74). Most paracenteses (66%) occurred ≤1 day after admission. In-hospital mortality was lower among patients who received early paracentesis than those who received it later (5.7% vs 8.1%; P=.049), although this difference was not significant after adjustment for confounders (OR, 1.26; 95% CI, 0.78–2.02). Among patients who underwent paracentesis, the mean hospital stay was 14% longer, and hospital charges were 29% greater than for patients that did not receive the procedure. Conclusions Paracentesis is underused for patients admitted to the hospital with ascites; the procedure is associated with increased short-term survival. These data support practice guidelines derived from expert opinion. Studies are needed to identify barriers to guideline adherence.