1361-P: Patients with Severe Nonalcoholic Steatohepatitis (NASH) Have Profound Insulin Resistance and Lipotoxicity
Authors: MARANGI STEPHEN A. , KALAVALAPALLI SRILAXMI , GODINEZ LEIVA EDDISON , THOMAIDES-BREARS HELENA B. , DIAMOND CHARLIE , MOHSENI YASMINE , GONZALEZ MARIA A. , ORTIZ ROCHA ANDREA , VALDEZ SAENZ ENRIQUE , SHRESTHA SULAV , MANSOUR LYDIA , SHETTY SHWETHA S. , CALVET MARIANNA M. , LOMONACO ROMINA , BARB DIANA , CUSI KENNETH 
Published: June 2023

NASH is the more severe form of nonalcoholic fatty liver disease (NAFLD), prone to advanced fibrosis/cirrhosis. However, the metabolic profile of such patients is not well characterized. The aim of this study was to assess the cardiometabolic features of patients with NASH matched for major variables (age, gender, BMI, A1c), to people with less severe disease activity and without NAFLD. To this end, we recruited 46 patients (age: 57±1.5 years; BMI: 36.2±0.8 kg/m2; A1c: 6.8±0.2%; T2DM: 70%), from our outpatient endocrine and PCP clinics and measured liver disease activity/severity by magnetic resonance (MR) iron corrected T1 imaging (cT1). Patients were grouped based on disease activity (cT1) into those without NAFLD (non-NAFLD; n = 8; cT1 &lt;800 ms), mild-to-moderate NASH (mNASH; n = 16; cT1 ≥800 to ≤875 ms), and severe/high-risk steatohepatitis (sNASH; n = 22; cT1 &gt;875 ms). Insulin resistance increased with the severity of NASH (HOMA-IR: non-NAFLD: 3.6±0.9 vs. mNASH: 4.3±0.7 vs. sNASH: 5.5±0.7), and so did adipose tissue IR (adipo-IR [fasting FFA x insulin]: 3.5±0.5 vs. 5.5±1.0 vs. 8.2±1.0; respectively, p=0.03). Dysfunctional adipose tissue/lipotoxicity was also evident from lower adiponectin levels (non-NAFLD: 7.4±2.4 vs. mNASH: 3.9±0.7 vs. sNASH: 3.7±0.3 µg/mL; p=0.04) and a 2-fold increase in ectopic fat/liver steatosis by MR-PDFF (mNASH: 11.2±0.9 vs. sNASH: 20.3±1.6; p&lt;0.001). Plasma CK-18, a marker of hepatocyte apoptosis, increased with NASH severity (105±13 vs. 220±44 vs. 361±57 U/L; respectively p=0.02) and correlated with the severity of NASH by cT1 (r=0.46; p&lt;0.01). Liver steatosis (r=0.73; p&lt;0.01) and adipo-IR (r=0.32; p=0.1) were also associated with cT1. Conclusion: Increased hepatic disease activity (cT1) in patients with NASH is a strong indicator of insulin resistance and an unfavorable cardiometabolic profile. Its use in the clinic may identify patients with a greater risk of adverse liver and cardiovascular outcomes.

Disclosure
S.A.Marangi: None. S.Shrestha: None. L.Mansour: None. S.S.Shetty: None. M.M.Calvet: None. R.Lomonaco: None. D.Barb: None. K.Cusi: Consultant; Poxel SA, Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns, Research Support; Echosens, Inventiva, LabCorp, Zydus. S.Kalavalapalli: None. E.Godinez leiva: None. H.B.Thomaides-brears: Employee; Perspectum Ltd., Stock/Shareholder; Perspectum Ltd. C.Diamond: Employee; Perspectum Ltd. Y.Mohseni: None. M.A.Gonzalez: None. A.Ortiz rocha: None. E.Valdez saenz: None.

Funding
National Institutes of Health (R01120331-01A1)