Browsing by Author "Ahmad, Jawad"
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Item Clinical Characteristics and HLA Associations of Azithromycin-Induced Liver Injury(Wiley, 2024) Conlon, Caroline; Li, Yi-Ju; Ahmad, Jawad; Barnhart, Huiman; Fontana, Robert J.; Ghabril, Marwan; Hayashi, Paul H.; Kleiner, David E.; Lee, William M.; Navarro, Victor; Odin, Joseph A.; Phillips, Elizabeth J.; Stolz, Andrew; Vuppalanchi, Raj; Halegoua-DeMarzio, Dina; Drug-Induced Liver Injury Network (DILIN); Medicine, School of MedicineBackground: Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug-induced liver injury (DILI) due to AZ. Methods: The clinical characteristics of individuals with definite, highly likely, or probable AZ-DILI enrolled in the US Drug-Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ-DILI cases was compared to population controls, other DILI cases, and other antibiotic-associated DILI cases. Results: Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ-DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA-DQA1*03:01 was significantly more common in AZ-DILI versus population controls and amoxicillin-clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively). Conclusion: Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA-DQA1*03:01 was significantly more common in AZ cases compared to controls.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 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 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.Item Value of liver biopsy in the diagnosis of drug-induced liver injury(Elsevier, 2022) Ahmad, Jawad; Barnhart, Huiman X.; Bonacini, Maurizio; Ghabril, Marwan; Hayashi, Paul H.; Odin, Joseph A.; Rockey, Don C.; Rossi, Simona; Serrano, Jose; Tillmann, Hans L.; Kleiner, David E.; Drug-Induced Liver Injury Network; Medicine, School of MedicineBackground & aims: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model. Methods: Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case. Results: Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients. Conclusions: Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis. Lay summary: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.