Browsing by Author "Szabo, Gyongyi"

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    Design of a multicenter randomized clinical trial for treatment of Alcohol-Associated Hepatitis
    (Elsevier, 2023-01-18) Tu, Wanzhu; Gawrieh, Samer; Dasarathy, Srinivasan; Mitchell, Mack C.; Simonetto, Douglas A.; Patidar, Kavish R.; McClain, Craig J.; Bataller, Ramon; Szabo, Gyongyi; Tang, Qing; Barton, Bruce A.; Radaeva, Svetlana; Sanyal, Arun J.; Shah, Vijay; Alcoholic Hepatitis Network (AlcHepNet) Investigators; Biostatistics, School of Public Health
    Background: Mortality is high for severe alcohol-associated hepatitis (AH). Corticosteroids are the standard of care for patients without contraindications. Recent data showed that interleukin-1β receptor antagonist anakinra attenuated inflammation and liver damage. We designed a multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of anakinra compared to prednisone. Methods: Patients meeting the clinical and biochemical criteria for severe AH with MELD scores between 20 and 35 were recruited at eight clinical sites. Eligible patients enrolled in the study were randomized to anakinra, 100 mg subcutaneous injection for 14 days, plus zinc sulfate 220 mg for 90 days, vs. prednisone 40 mg PO daily for 30 days. Matching placebos for anakinra, zinc, and prednisone were provided to mask the treatment. Participants were followed for 180 days. The primary outcome was overall survival at 90 days. An unadjusted log-rank test was used to compare the survival of the two treatments in the first 90 days. Between July 10, 2020, and March 4, 2022, we screened 1082 patients with severe AH, and 147 eligible patients were enrolled and randomized. The average baseline MELD score was 25 [range 20-35], Maddrey discriminant function (MDF) was 59.4 [range 20.2-197.5]. The mean aspartate transaminase (AST)-to-alanine transaminase (ALT) ratio was 3.5. The baseline characteristics were not statistically different between the two treatment groups. Conclusions: The study provided a direct comparison of the survival benefits and safety profiles of anakinra plus zinc vs. prednisone in patients with severe AH.
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    Introducing the 2019 American Association for the Study of Liver Diseases Guidance on Alcohol‐Associated Liver Disease
    (Wiley, 2020-01) Lucey, Michael Ronan; Im, Gene Y.; Mellinger, Jessica L.; Szabo, Gyongyi; Crabb, David W.; Medicine, School of Medicine
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    Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis
    (Wiley, 2022) Hu, Kunpeng; Perez-Matos, Maria C.; Argemi, Josepmaria; Vilar-Gomez, Eduardo; Shalaurova, Irina; Bullitt, Esther; Landeen, Lee; Sugahara, Go; Deng, Huiyan; Mathur, Karan; Tran, Stephanie; Cai, Huimei; He, Hanchang; Yalcin, Yusuf; Barbosa, Joana Vieira; Ventura-Cots, Meritxell; Marx, Katherine; Gad, Aniket P.; Niezen, Sebastian; Barba, Sofia Izunza; Ang, Lay-Hong; Popov, Yury V.; Fricker, Zachary; Lai, Michelle; Curry, Michael; Afdhal, Nezam; Szabo, Gyongyi; Mukamal, Kenneth J.; Sanyal, Arun J.; Otvos, James D.; Malik, Raza; Saito, Takeshi; Connelly, Margery A.; Chalasani, Naga P.; Bataller, Ramon; Jiang, Z. Gordon; Medicine, School of Medicine
    Background and aims: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation. Approach and results: We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z. Conclusions: Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.
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    Research methodologies to address clinical unmet needs and challenges in alcohol-associated liver disease
    (Wolters Kluwer, 2022) Singal, Ashwani K.; Kwo, Paul; Kwong, Allison; Liangpunsakul, Suthat; Louvet, Alexandre; Mandrekar, Pranoti; McClain, Craig; Mellinger, Jessica; Szabo, Gyongyi; Terrault, Norah; Thursz, Mark; Winder, Gerald S.; Kim, W. Ray; Shah, Vijay H.; Medicine, School of Medicine
    Alcohol-associated liver disease (ALD) is emerging worldwide as the leading cause of liver-related morbidity, mortality, and indication for liver transplantation. The ALD Special Interest Group and the Clinical Research Committee at the digital American Association for the Study of Liver Diseases meeting in November 2020 held the scientific sessions to identify clinical unmet needs in ALD, and addressing these needs using clinical research methodologies. Of several research methodologies, the sessions were focused on (a) studying disease burden of ALD using large administrative databases, (b) developing biomarkers for noninvasive diagnosis of alcohol-associated hepatitis (AH) and estimation of disease prognosis, (c) identifying therapeutic targets for ALD and AH, (d) deriving accurate models to predict prognosis or posttransplant alcohol relapse as a basis for developing treatment algorithm and a uniform protocol on patient-selection criteria for liver transplantation, and (e) examining qualitative research methodologies in studying the barriers to implementation of multidisciplinary integrated care model by hepatology and addiction teams for the management of dual pathology of liver disease and of alcohol use disorder. Prospective multicenter studies are required to address many of these clinical unmet needs. Further, multidisciplinary care models are needed to improve long-term outcomes in patients with ALD.