Letter to the Editor: 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
Authors: Dong Ji, Mingjie Zhang, Enqiang Qin, Lunqing Zhang, Jing Xu, Yudong Wang, Gregory Cheng, Feng Wang, George Lau
Journal: Metabolism (2020)

Obesity [[1]Palaiodimos L. Kokkinidis D.G. Li W. Karamanis D. Ognibene J. Arora S. et al.Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx.New York Metabolism. 2020; 108 (Epub 2020/05/19): 154262https://doi.org/10.1016/j.metabol.2020.154262Abstract Full Text Full Text PDF Scopus (576) Google Scholar,[2]Zheng K.I. Gao F. Wang X. Sun Q. Pan K. Wang T. et al.Obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease.Metabolism. 2020; 108: 154244https://doi.org/10.1016/j.metabol.2020.154244Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar], diabetes [[3]Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. et al.China medical treatment expert group for C. clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; (Epub ahead of print)https://doi.org/10.1056/NEJMoa2002032Crossref Scopus (20093) Google Scholar,[4]Yang X. Yu Y. Xu J. Shu H. Xia J. Liu H. et al.Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.Lancet Respir Med. 2020; (Feb 24. pii:S22132600)https://doi.org/10.1016/S2213-2600(20)30079-5Abstract Full Text Full Text PDF Scopus (6897) Google Scholar], non-alcoholic fatty liver disease (NAFLD) [[5]Ji D. Qin E. Xu J. Zhang D. Cheng G. Wang Y. et al.Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study.J Hepatol. 2020 Apr 8; S0168-8278: 302063https://doi.org/10.1016/j.jhep.2020.03.044Abstract Full Text Full Text PDF Scopus (382) Google Scholar] and metabolic dysfunction associated fatty liver disease (MAFLD) [[6]Targher G. Mantovani A. Byrne C.D. Wang X.B. Yan H.D. Sun Q.F. et al.Risk of severe illness from COVID-19 in patients with metabolic dysfunction-associated fatty liver disease and increased fibrosis scores.Gut. 2020 Aug; 69 ([Epub 2020 May 15]): 1545-1547https://doi.org/10.1136/gutjnl-2020-321611Crossref PubMed Scopus (147) Google Scholar,[7]Sharma P. Kumar A. Metabolic dysfunction associated fatty liver disease increases risk of severe Covid-19.Diabetes Metab Syndr. 2020 Sep-Oct; 14 ([Epub 2020 Jun 10]): 825-827https://doi.org/10.1016/j.dsx.2020.06.013Crossref PubMed Scopus (41) Google Scholar] 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 [8Llitjos J.F. Leclerc M. Chochois C. Monsallier J.M. Ramakers M. Auvray M. et al.High incidence of venous thromboembolic events in anticoagulated severe COVID19 patients JTH.2020https://doi.org/10.1111/JTH.14869Crossref Google Scholar, 9Cui S. Chen S. Li X. Liu S. Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 1421-1424Crossref PubMed Scopus (1283) Google Scholar, 10Zhang L. Feng X. Zhang D. Jiang C. Mei H. Wang J. et al.Deep vein thrombosis in hospitalized patients with coronavirus disease 2019 (COVID-19) in Wuhan, China: prevalence, risk factors, and outcome.Circulation. 2020; https://doi.org/10.1161/CIRCULATIONAHA.120.046702Crossref Scopus (121) Google Scholar]. 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]Cui S. Chen S. Li X. Liu S. Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 1421-1424Crossref PubMed Scopus (1283) Google Scholar,[10]Zhang L. Feng X. Zhang D. Jiang C. Mei H. Wang J. et al.Deep vein thrombosis in hospitalized patients with coronavirus disease 2019 (COVID-19) in Wuhan, China: prevalence, risk factors, and outcome.Circulation. 2020; https://doi.org/10.1161/CIRCULATIONAHA.120.046702Crossref Scopus (121) Google Scholar]. 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]Verrijken A.F.S. Mertens I. Prawitt J. Caron S. Hubens G. Van Marck E. et al.Prothrombotic factors in histologically proven NAFLD and NASH.Hepatology. 2014; 59: 121-129Crossref PubMed Scopus (131) Google Scholar]. It may be possible that the hypercoagulable state in NAFLD contributes 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]Cui S. Chen S. Li X. Liu S. Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 1421-1424Crossref PubMed Scopus (1283) Google Scholar] and compared the D-dimer levels of NAFLD subjects (n = 75) with non-NAFLD subjects(n = 125) from our previous COVID-19 cohort [[5]Ji D. Qin E. Xu J. Zhang D. Cheng G. Wang Y. et al.Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study.J Hepatol. 2020 Apr 8; S0168-8278: 302063https://doi.org/10.1016/j.jhep.2020.03.044Abstract Full Text Full Text PDF Scopus (382) Google Scholar]. NAFLD was identified as hepatic steatosis index more than 36 points from records of 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 μg/ml vs 0.80 ± 1.2 μg/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 NAFLD (n = 125), 0.72 ± 1.10 μg/ml vs 0.38 ± 0.46 μg/ml, p = 0.003 and 1.81 ± 4.1 mg/ml vs 0.63 ± 0.41 mg/ml, p = 0.003 respectively (Table1). 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]Ackermann M. Verleden S.E. Kuehnel M. Haverich A. Welte T. Laenger F. et al.Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.N Engl J Med. 2020 Jul 9; 383 ([Epub 2020 May 21]): 120-128https://doi.org/10.1056/NEJMoa2015432Crossref PubMed Scopus (3796) Google Scholar]. 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 S. Skok K. Zechner P. Kessler H. Kaufman F. Koelblinger C. et al.Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center, clinicopathologic case series.Ann Intern Med. 2020; 173: 350-361https://doi.org/10.7326/M20-2566Crossref PubMed Scopus (572) Google Scholar]. 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]Falasca L. Nardacci R. Colombo N. Lalle E. Di Caro A. Nicastri E. et al.Post-mortem findings in italian patients with COVID-19 – a descriptive full autopsy study of cases with and without co-morbidities.The Journal of Infectious Diseases. 2020 Sep 11; https://doi.org/10.1093/infdis/jiaa578Crossref PubMed Scopus (137) Google Scholar]. Similarly, pulmonary thrombi and hepatic steatosis were present in 73% and 55% of COVID-19 patients in an Italian post-mortem series [[15]Braunersreuther V. Viviani G.L. Mach F. Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease.World J Gastroenterol. 2012 Feb 28; 18: 727-735Crossref PubMed Scopus (263) Google Scholar]. 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 (Table 1).Table 1Association of VTE with elevation of D-dimers and NAFLD in the UH COVID-19 cohort [[9]Cui S. Chen S. Li X. Liu S. Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 1421-1424Crossref PubMed Scopus (1283) Google Scholar].VTE(n = 21)Non-VTE(n = 60)P valuesD-Dimer levels (μg/ml) at admission5.2 ± 2.790.8 ± 1.20.001BMI24.6 ± 2.6523.9 ± 1.90.27NAFLD76% (16/21)45% (27/60)0.01Association of NAFLD with elevation of D-dimers in the FYSPH -PLAGHCOVID-19 cohort [[5]Ji D. Qin E. Xu J. Zhang D. Cheng G. Wang Y. et al.Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study.J Hepatol. 2020 Apr 8; S0168-8278: 302063https://doi.org/10.1016/j.jhep.2020.03.044Abstract Full Text Full Text PDF Scopus (382) Google Scholar].Non-NAFLD(n = 125)NAFLD(n = 75)p values (multivariate)D-Dimer(ug/ml) Admission0.38 ± 0.460.72 ± 1.100.003 (0.046)Peak0.63 ± 0.411.81 ± 4.10.003 (0.028) Open table in a new tab This study was conducted according to the 1975 Declaration of Helsinki and approved by the ethics committee of Union Hospital, the Fifth Medical Center of Chinese PLA General Hospital and Fuyang Second People's Hospital. Written informed consent was waived in view of the status of designated centre for new emerging infectious diseases of the three participating hospitals. Patients or the public WERE NOT involved in the design, or conduct, or reporting, or dissemination plans of our research. DJ, EQ, JX and FW treated the patients and collected the epidemiological and clinical data. DJ, YW, MZ and LZ processed statistical data and drafted the manuscript. GC and GL had the idea for and designed the study. GC, FW and GL revised the final manuscript and are responsible for summarizing all the data. We declare no competing interests. This work is funded by the Key Project of Jumei Special Fund for Hepatobiliary Disease Prevention and Treatment (2018JM12603003). We acknowledge all health-care workers involved in the diagnosis and treatment of patients with COVID-19 in our hospitals.