key: cord-1008797-f4svwtc3
authors: Ji, Dong; Zhang, Mingjie; Qin, Enqiang; Zhang, Lunqing; Xu, Jing; Wang, Yudong; Cheng, Gregory; Wang, Feng; Lau, George
title: Obesity, Diabetes, Non-alcoholic Fatty Liver Disease and Metabolic Dysfunction Associated Fatty Liver Disease are Proinflammatory Hypercoagulable States associated with Severe Disease and Thrombosis in Covid-19
date: 2020-11-19
journal: Metabolism
DOI: 10.1016/j.metabol.2020.154437
sha: 2a8ef8a0128f84011c22e2b4b1907879cf0c4bb4
doc_id: 1008797
cord_uid: f4svwtc3

nan

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We declare no competing interests. Obesity [1, 2] , diabetes [3, 4] , non-alcoholic fatty liver disease (NAFLD) [5] and metabolic dysfunction associated fatty liver disease (MAFLD) [6, 7] are associated with severe Disease in Covid-19. High incidence (25-70%) of deep vein thrombosis (DVT) had been reported in patients with severe COVID-19, particularly among those admitted to the intensive care units [8] [9] [10] . Obesity (BMI ≥30), Padua score>4 and D-dimer >1.0 (μg/ml) were associated with DVT in COVID-19 patients in multivariant analysis [9, 10] . It had been suggested that patients with NAFLD were characterized by a hypercoagulable state, with elevated plasma levels of von Willebrand factor, enhanced platelets activation, and increased levels of circulating plasminogen activator inhibitor type 1 (PAI-1) [11] . It may be possible that the hypercoagulable state in NAFLD contribute to the high incidence of thrombosis in COVID-19 subjects. We retrospectively studied the prevalence of NAFLD among our cohort of COVID-19 patients with doppler ultrasound documented deep vein thrombosis (DVT) [9] and compared the D-dimer levels of NAFLD subjects (n=75) with non-NAFLD subjects(n=125) from our previous COVID-19 cohort [5] . NAFLD was identified as hepatic steatosis index more than 36 points from records on the patients before and within 12 months of the diagnosis of COVID-19 and/or by abdominal ultrasound examination. NAFLD was present in 76% (16/21) of COVID-19 DVT subjects as compared with 45% prevalence(27/60) in non-DVT subjects, p=0.01 Alternatively, DVT was detected in 37.2% (16/43) and 13.2% (5/38) of NAFLD and non-NAFLD COVID-19 subjects respectively (p=0.01).

The mean admission D-dimers levels of the 21 DVT patients was significantly higher than that of non-DVT subjects (5.20 ± 2.79 ug/ml vs 0.80 ± 1.2 ug/ml, p<0.001). Mean admission and peak D-dimer levels were significantly higher in COVID-19 subjects with NAFLD (n=75) as compared with those without J o u r n a l P r e -p r o o f Journal Pre-proof NAFLD (n=125), 0.72 ± 1.10 ug/ml vs 0.38 ± 0.46 ug/ml, p=0.003 and 1.81 ± 4.1mg/ml vs 0.63 ± 0.41mg/ml, p=0.003 respectively. The association of NAFLD with admission and peak D-dimer levels remain significant in multivariate analysis, p=0.046 and p=0.028, respectively. BMI, age>60, other comorbidities were no longer associated with elevated D-dimer levels at admission in multivariate analysis. The liver is a frontline immune organ and increased production of pro-inflammatory cytokines by adipose and Kupffer cells had been reported in NAFLD patients [12] . During the SARS-CoV-2 infection, there may further increased production of IL6, IL8, TNF-α in NAFLD subjects and higher likelihood of activation of the coagulation cascade by pro-inflammatory cytokines and subsequent thrombosis. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy [13] . Lax et al reported hepatic steatosis, involving 50% to 60% of the hepatocytes, in all 12 COVID-19 patients with pulmonary embolism at autopsies [14] . 14 Similarly, pulmonary thrombi and hepatic steatosis were present in 73% and 55% of COVID-19 patients in an Italian post-mortem series [15] . Obesity and diabetes are also risk factors for NAFLD, MAFLD, and thrombosis. It is possible that these diseases are interlinked and the common pathophysiological pathway for predisposing to severe COVID-19 is a proinflammatory hypercoagulable state contributing to thrombosis and disease progression. J o u r n a l P r e -p r o o f

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