Dear Sir,
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 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] 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 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]. 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]. 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 (Table 1).
Table 1.
Association of VTE with elevation of D-dimers and NAFLD in the UH COVID-19 cohort [9].
| VTE (n = 21) |
Non-VTE (n = 60) |
P values | |
|---|---|---|---|
| D-Dimer levels (μg/ml) at admission | 5.2 ± 2.79 | 0.8 ± 1.2 | 0.001 |
| BMI | 24.6 ± 2.65 | 23.9 ± 1.9 | 0.27 |
| NAFLD | 76% (16/21) | 45% (27/60) | 0.01 |
| Association of NAFLD with elevation of D-dimers in the FYSPH -PLAGH COVID-19 cohort [5]. | |||
|---|---|---|---|
| Non-NAFLD (n = 125) |
NAFLD (n = 75) |
p values (multivariate) | |
| D-Dimer(ug/ml) Admission | 0.38 ± 0.46 | 0.72 ± 1.10 | 0.003 (0.046) |
| Peak | 0.63 ± 0.41 | 1.81 ± 4.1 | 0.003 (0.028) |
Ethical approval and Informed consent
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 and public involvement
Patients or the public WERE NOT involved in the design, or conduct, or reporting, or dissemination plans of our research.
CRediT authorship contribution statement
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.
Declaration of competing interest
We declare no competing interests.
Acknowledgments
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.
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