Browsing by Author "Gu, Jiezhun"
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Item Amoxicillin-Clavulanate-Induced Liver Injury(Springer, 2016-08) deLomos, Andrew S.; Ghabril, Marwan; Rockey, Don C.; Gu, Jiezhun; Barnhart, Huiman X.; Fontana, Robert J.; Kleiner, David E.; Bonkovsky, Herbert L.; Department of Medicine, IU School of MedicineBackground and Aims Amoxicillin–clavulanate (AC) is the most frequent cause of idiosyncratic drug-induced injury (DILI) in the US DILI Network (DILIN) registry. Here, we examined a large cohort of AC-DILI cases and compared features of AC-DILI to those of other drugs. Methods Subjects with suspected DILI were enrolled prospectively, and cases were adjudicated as previously described. Clinical variables and outcomes of patients with AC-DILI were compared to the overall DILIN cohort and to DILI caused by other antimicrobials. Results One hundred and seventeen subjects with AC-DILI were identified from the cohort (n = 1038) representing 11 % of all cases and 24 % of those due to antimicrobial agents (n = 479). Those with AC-DILI were older (60 vs. 48 years, P < 0.001). AC-DILI was more frequent in men than women (62 vs. 39 %) compared to the overall cohort (40 vs. 60 %, P < 0.001). The mean time to symptom onset was 31 days. The Tb, ALT, and ALP were 7 mg/dL, 478, and 325 U/L at onset. Nearly all liver biopsies showed prominent cholestatic features. Resolution of AC-DILI, defined by return of Tb to <2.5 mg/dL, occurred on average 55 days after the peak value. Three female subjects required liver transplantation, and none died due to DILI. Conclusion AC-DILI causes a moderately severe, mixed hepatocellular–cholestatic injury, particularly in older men, unlike DILI in general, which predominates in women. Although often protracted, eventual apparent recovery is typical, particularly for men and usually in women, but three women required liver transplantation.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 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 Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury(Elsevier, 2023) Chalasani, Naga; Li, Yi-Ju; Dellinger, Andrew; Navarro, Victor; Bonkovsky, Herbert; Fontana, Robert J.; Gu, Jiezhun; Barnhart, Huiman; Phillips, Elizabeth; Lammert, Craig; Schwantes-An, Tae-Hwi; Nicoletti, Paola; Kleiner, David E.; Hoofnagle, Jay H.; Drug Induced Liver Injury Network; Medicine, School of MedicineBackground & aims: Nitrofurantoin (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). Methods: Seventy-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). Results: Liver 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). Conclusion: NTF-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 implications: Nitrofurantoin 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.Item Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements(Wiley, 2017-04) Bonkovsky, Herbert L.; Kleiner, David E.; Gu, Jiezhun; Odin, Joseph A.; Russo, Mark W.; Navarro, Victor M.; Fontana, Robert J.; Ghabril, Marwan S.; Barnhart, Huiman; Hoofnagle, Jay H.; U.S. Drug Induced Liver Injury Network Investigators; Medicine, School of MedicineBile duct loss during the course of drug-induced liver injury is uncommon, but can be an indication of vanishing bile duct syndrome (VBDS). In this work, we assess the frequency, causes, clinical features, and outcomes of cases of drug-induced liver injury with histologically proven bile duct loss. All cases of drug-induced liver injury enrolled into a prospective database over a 10-year period that had undergone liver biopsies (n = 363) were scored for the presence of bile duct loss and assessed for clinical and laboratory features, causes, and outcomes. Twenty-six of the 363 patients (7%) with drug-, herbal-, or dietary-supplement-associated liver injury had bile duct loss on liver biopsy, which was moderate to severe (<50% of portal areas with bile ducts) in 14 and mild (50%-75%) in 12. The presenting clinical features of the 26 cases varied, but the most common clinical pattern was a severe cholestatic hepatitis. The implicated agents included amoxicillin/clavulanate (n = 3), temozolomide (n = 3), various herbal products (n = 3), azithromycin (n = 2), and 15 other medications or dietary supplements. Compared to those without, those with bile duct loss were more likely to develop chronic liver injury (94% vs. 47%), which was usually cholestatic and sometimes severe. Five patients died and 2 others underwent liver transplantation for progressive cholestasis despite treatment with corticosteroids and ursodiol. The most predictive factor of poor outcome was the degree of bile duct loss on liver biopsy. CONCLUSION: Bile duct loss during acute cholestatic hepatitis is an ominous early indicator of possible VBDS, for which at present there are no known means of prevention or therapy.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 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 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 Heavy Consumption of Alcohol is Not Associated With Worse Outcomes in Patients With Idiosyncratic Drug-induced Liver Injury Compared to Non-Drinkers(Elsevier, 2018-05) Dakhoul, Lara; Ghabril, Marwan; Gu, Jiezhun; Navarro, Victor; Chalasani, Naga; Serrano, Jose; Medicine, School of MedicineBACKGROUND & AIMS: The relationship between alcohol consumption and idiosyncratic drug-induced liver injury (DILI) is not well understood. We investigated the relationship between heavy consumption of alcohol and characteristics and outcomes of patients with DILI enrolled in the Drug-induced Liver Injury Network (DILIN) prospective study. METHODS: We collected data from 1198 individuals with definite, highly likely, or probable DILI enrolled in the DILIN study from September 2004 through April 2016. At enrollment, all participants were asked about alcohol consumption; those with any alcohol consumption during previous 12 months were asked to complete the Skinner questionnaire to assess drinking history. Heavy consumption of alcohol was defined as more than 3 drinks, on average, per day by men or more than 2 drinks, on average, per day by women. RESULTS: Of the 601 persons who reported consuming at least 1 alcoholic drink in the preceding 12 months, 348 completed the Skinner questionnaire and 80 reported heavy consumption of alcohol. Heavy drinkers were younger (average age, 42 years) than non-drinkers (average age, 49 years) and a higher proportion were men (63% of heavy drinkers vs 35% of nondrinkers) (P < .01 for each comparison). Anabolic steroids were the most common cause of DILI among heavy drinkers (in 13% vs 2% in non-drinkers) (P < .001). Heavy drinkers had significantly higher peak serum levels of alanine aminotransferase (1323 U/L) than non-drinkers (754 U/L) (P = .02) and higher levels of bilirubin (16.1 mg/dL vs 12.7 mg/dL in non-drinkers) (P = .03) but there was no significant difference in liver-related death or liver transplantation between heavy drinkers (occurred in 10%) vs non-drinkers (occurred in 6%) (P = .18). CONCLUSION: In an analysis of data from the DILIN, we found anabolic steroids to be the most common cause of DILI in individuals who are heavy consumers of alcohol. Compared to non-drinkers, DILI was not associated with a greater proportion of liver-related deaths or liver transplantation in heavy drinkers.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.