Letter to the Editor: Obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease
Authors: Kenneth I. Zheng, Feng Gao, Xiao-Bo Wang, Qing-Feng Sun, Ke-Hua Pan, Ting-Yao Wang, Hong-Lei Ma, Yong-Ping Chen, Wen-Yue Liu, Jacob George, Ming-Hua Zheng
Journal: Metabolism (2020)

Coronavirus disease 2019 (COVID-19) has been declared a pandemic in 2020 [1WHO characterizes COVID-19 as a pandemic.https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happenDate: March 13, 2020Date accessed: March 18, 2020Google Scholar]. Preliminary data suggests that obesity may aggravate the severity of respiratory diseases and of COVID-19 [2Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; (In press)https://doi.org/10.1056/NEJMoa2002032Crossref Scopus (20405) Google Scholar]. Patients with metabolic associated fatty liver disease (MAFLD) [3Eslam M. Newsome P.N. Anstee Q.M. Targher G. Gomez M.R. Zelber-Sagi S. et al.A new definition for metabolic associated fatty liver disease: an international expert consensus statement.J Hepatol. 2020; https://doi.org/10.1016/j.jhep.2020.03.039Abstract Full Text Full Text PDF PubMed Scopus (2259) Google Scholar], formerly known as non-alcoholic fatty liver disease, are often obese and have additional metabolic risk factors which may translate to a greater risk from respiratory diseases [4Arias-Loste M.T. Fábrega E. López-Hoyos M. Crespo J. The crosstalk between hypoxia and innate immunity in the development of obesity-related nonalcoholic fatty liver disease.Biomed Res Int. 2015; 2015: 319745Crossref PubMed Scopus (19) Google Scholar, 5Lee C.H. Choi S.H. Chung G.E. Park B. Kwak M.S. Nonalcoholic fatty liver disease is associated with decreased lung function.Liver Int. 2018; 38: 2091-2100Crossref PubMed Scopus (25) Google Scholar, 6Nseir W.B. Mograbi J.M. Amara A.E. Abu Elheja O.H. Mahamid M.N. Non-alcoholic fatty liver disease and 30-day all-cause mortality in adult patients with community-acquired pneumonia.Qjm. 2019; 112: 95-99Crossref PubMed Scopus (36) Google Scholar, 7Peng T.C. Kao T.W. Wu L.W. Chen Y.J. Chang Y.W. Wang C.C. et al.Association between pulmonary function and nonalcoholic fatty liver disease in the NHANES III Study.Medicine (Baltimore). 2015; 94: e907Crossref PubMed Scopus (22) Google Scholar]. It is currently not known whether MALFD patients are also more likely to have greater COVID-19 severity of illness. This study investigated the association between MAFLD and COVID-19 severity. We consecutively enrolled 214 patients with laboratory-confirmed COVID-19 aged between 18 and 75 years from three hospitals in Wenzhou, China (the First Affiliated Hospital of Wenzhou Medical University, Wenzhou Central Hospital, and Ruian People's Hospital) between January 17, 2020 and February 11, 2020. All patients were screened for fatty liver by computed tomography and subsequently diagnosed as MAFLD according to a recent set of consensus diagnostic criteria [3Eslam M. Newsome P.N. Anstee Q.M. Targher G. Gomez M.R. Zelber-Sagi S. et al.A new definition for metabolic associated fatty liver disease: an international expert consensus statement.J Hepatol. 2020; https://doi.org/10.1016/j.jhep.2020.03.039Abstract Full Text Full Text PDF PubMed Scopus (2259) Google Scholar]. Sixty six COVID-19 patients with MAFLD were included in the analyses and were divided into two groups [those with obesity (n = 45) and those without (n = 21)]. All patients received standard treatment based on the COVID-19 Management Guidance (7th edition) [8National Health Commission & State Administration of Traditional Chinese Medicine Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).2020Google Scholar]. This study was approved by the local ethics review boards of all three hospitals. The requirement for written informed consent was waived for use of the de-identified data. COVID-19 was diagnosed as a positive result by high-throughput sequencing or real-time reverse transcriptase-polymerase chain reaction assay of oropharyngeal swab specimens. COVID-19 severity was assessed during hospitalization and classified as severe and non-severe based on the management guideline [8National Health Commission & State Administration of Traditional Chinese Medicine Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7).2020Google Scholar]. Blood routine markers were analyzed at the central laboratory of respective hospital using standard methods by VITROS 5600 Integrated Immunodiagnostic System (VITROS 5600, Johnson, New Jersey, USA). We collected demographic information and past medical history from all patients. Laboratory parameters were tested on the first day of hospital admission. Body weight and height were measured by trained examiners on admission. Body mass index (BMI) was calculated using the formula weight (kilograms) divided by height (meters) squared. Obesity was defined as BMI >25 kg/m2 [9Goda A. Masuyama T. Obesity and overweight in Asian people.Circ J. 2016; 80: 2425-2426Crossref PubMed Scopus (25) Google Scholar]. Diabetes, hypertension and dyslipidemia were diagnosed based on established criteria [10Alberti K.G. Zimmet P. Shaw J. Metabolic syndrome—a new world-wide definition. A consensus statement from the International Diabetes Federation.Diabet Med. 2006; 23: 469-480Crossref PubMed Scopus (4829) Google Scholar]. All patients denied a history of chronic obstructive or restrictive pulmonary disease. Continuous variables are expressed as mean ± SD and compared using either the Student's t-test for normally distributed variables or the Mann-Whitney test for non-normally distributed variables. Continuous variables were tested for normality using the Shapiro-Wilk test. Differences between categorical variables were examined with the chi-squared test or the Fisher's exact test as appropriate. The association between obesity (as exposure) and COVID-19 severity (as the outcome) among MAFLD patients was assessed by binary logistic regression. Statistical analyses were two-sided and significance was set at p < 0.05. All statistical tests were performed using SPSS version 23.0 (SPSS Inc., Chicago, USA). The mean age of enrolled patients was 47 years and 74.2% were female. Table 1 shows the main clinical and biochemical characteristics of COVID-19 patients with MAFLD stratified by obesity status. Mean BMI for the non-obese and obese patients were 22.7 ± 2.1 kg/m2 and 28.3 ± 3.2 kg/m2, respectively. Compared with the non-obese group, obese patients had higher levels of aspartate aminotransferase, fasting blood glucose and LDL-cholesterol, and lower lymphocyte counts. Notably, MALFD patients that were obese had more severe COVID-19 disease (37.5% vs. 9.5%, p = 0.021).Table 1Baseline characteristics of MAFLD patients with laboratory-confirmed COVID-19 according to obesity status.OverallN = 66Without obesityN = 21With obesityN = 45P valueDemographics Age, years18–44 yrs, n (%)39 (59.1%)15 (71.43%)24 (53.33%)0.20745–64 yrs, n (%)22 (33.3%)6 (28.57%)16 (35.56%)≥65 yrs, n (%)5 (7.6%)0 (0.00%)5 (11.11%) Female sex, n (%)17 (25.8%)4 (19.05%)13 (28.89%)0.548 Body mass index, kg/m226.5 ± 3.922.7 ± 2.128.3 ± 3.2<0.001Coexisting disorders Current smoker, n (%)8 (12.1%)2 (9.5%)6 (13.3%)0.659 Type 2 diabetes, n (%)16 (24.2%)2 (9.5%)14 (31.1%)0.070 Hypertension, n (%)19 (28.8%)3 (14.3%)16 (35.6%)0.089 Dyslipidemia, n (%)45 (68.2%)14 (66.67%)31 (68.89%)0.857Laboratory parameters White blood cell count, ×1094.9 (3.9–6.7)4.8 (3.8–6.3)5.0 (4.1–6.7)0.495>10 × 109, n (%)2 (3.0%)0 (0.0%)2 (4.4%)0.511<4 × 109, n (%)17 (25.8%)7 (33.3%)10 (22.2%) Lymphocyte count, ×1091.2 (0.9–1.6)1.4 (1.1–1.8)1.1 (0.9–1.4)0.040<1.5 × 109, n (%)47 (71.2%)11 (52.4%)36 (80.0%)0.021 C-reactive protein, mg/L21.6 (8.1–47.3)18.3 (5.8–24.5)25.3 (11.3–53.5)0.097≥10 mg/L, n (%)47 (71.2%)13 (61.9%)34 (75.6%)0.382 Alanine aminotransferase, U/L29.5 (24.0–62.5)26.0 (20.0–45.0)30.0 (24.0–65.0)0.150>40 U/L, n (%)25 (37.9%)6 (28.6%)19 (42.2%)0.415 Aspartate aminotransferase, U/L31.5 (23.0–47.0)25.0 (21.0–33.0)35.0 (27.0–52.0)0.010>40 U/L, n (%)20 (30.3%)2 (9.5%)18 (40.0%)0.020 Total bilirubin, μmol/L13.3 (9.3–17.1)15.6 (11.8–19.3)11.5 (8.8–16.7)0.051 Creatinine, μmol/L74.0 (65.5–83.0)78.0 (67.0–87.0)74.0 (65.0–82.0)0.401 Fasting blood glucose, mmol/L6.7 ± 2.35.8 ± 1.57.1 ± 2.60.047 HbA1c, %1.5 ± 0.61.3 ± 0.61.5 ± 0.60.145 Triglycerides, mmol/L3.9 ± 0.93.7 ± 0.94.1 ± 0.90.086 Total cholesterol, mmol/L1.0 ± 0.31.1 ± 0.21.0 ± 0.30.255 HDL-cholesterol, mmol/L2.3 ± 0.92.0 ± 0.92.4 ± 0.80.074 LDL-cholesterol, mmol/L7.0 ± 1.15.7 ± 0.57.3 ± 1.10.032COVID-19 severity, n (%)0.021 Non-severe47 (71.2%)19 (90.5%)28 (62.2%) Severe19 (28.8%)2 (9.5%)17 (37.8%)Data are expressed as mean ± SD, medians and inter-quartile range or percentage. Open table in a new tab Data are expressed as mean ± SD, medians and inter-quartile range or percentage. As shown in Supplementary Table 1, there were 47 (71.2%) patients with non-severe COVID-19 and 19 (28.8%) with severe COVID-19. Compared to those with non-severe COVID-19, patients with severe disease were more obese (89.5% vs. 59.6%, p = 0.021). They were also more likely to be smokers (26.3% vs. 6.4%, p = 0.038), and had higher C-reactive protein concentrations (median 52.7 [IQR 33.5–74.9] vs. 18.3 [4.6–24.9], p < 0.001) and lower lymphocyte counts (median 1.0 [IQR 0.8–1.2] vs. 1.4 [1.1–1.7], p = 0.005). As shown in Table 2, in the unadjusted logistic regression model with COVID-19 severity as the outcome, the presence of obesity in MAFLD patients was associated with a ~6-fold increased risk of severe COVID-19 illness (unadjusted OR 5.77, 95% CI 1.19–27.91, p = 0.029). Notably, this association with obesity and COVID-19 severity remained significant (adjusted-OR 6.32, 95%CI 1.16–34.54, p = 0.033) even after adjusting for age, sex, smoking, diabetes, hypertension, and dyslipidaemia.Table 2Multivariable-adjusted association between obesity (as exposure) and COVID-19 severity (as the outcome) in patients with MAFLD.OR95% CIP valueUnadjusted5.771.19–27.910.029Adjusted model I6.251.23–31.710.027Adjusted model II6.321.16–34.540.033Model 1: adjusted for age and sex.Model 2: adjusted for age, sex, smoking, type 2 diabetes, hypertension, and dyslipidemia. Open table in a new tab Model 1: adjusted for age and sex. Model 2: adjusted for age, sex, smoking, type 2 diabetes, hypertension, and dyslipidemia. Our results show that in MAFLD patients with laboratory-confirmed COVID-19, the presence of obesity markedly increases the risk of having severe illness. This association remained significant after adjusting for likely confounders. We reported previously that obesity is associated with a nearly 3-fold increased risk for severe COVID-19 with a dose-effect relationship between increasing BMI and the proportion of patients with severe illness [11Gao F. Zheng K.I. Wang X.-B. Sun Q.-F. Pan K.-H. Wang T.-Y. et al.Obesity is a risk factor for greater COVID-19 severity.Diabetes Care. 2020; Crossref Scopus (291) Google Scholar]. In the current analysis, the risk of severe illness in MAFLD patients with co-existing obesity was >6-fold greater after adjustment for confounders. These findings are distinct, suggesting that the risk of obesity to COVID-19 severity is significantly greater in those with MAFLD. However, the virological and physiological mechanisms underlying the relationship we observed are not clarified by the present data. Systemic inflammatory response syndrome, a common complication in severe COVID-19 [12Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (33099) Google Scholar], is promoted by the activation of CD14+ and CD16+ inflammatory monocytes producing a larger amount of interleukin (IL)-6 and other proinflammatory factors. This suggests IL-6 is a key proinflammatory factor that triggers the inflammatory "storm" in patients [13Feng G. Zheng K.I. Yan Q.Q. Rios R.S. Targher G. Byrne C.D. et al.COVID-19 and liver dysfunction: current insights and emergent therapeutic strategies.J Clin Transl Hepatol. 2020; 8: 18-24Crossref PubMed Scopus (309) Google Scholar]. In MAFLD patients, particularly those with obesity, increased inflammatory activity in the liver and visceral fat is independently correlated with increased levels of IL-6 [14van der Poorten D. Milner K.L. Hui J. Hodge A. Trenell M.I. Kench J.G. et al.Visceral fat: a key mediator of steatohepatitis in metabolic liver disease.Hepatology. 2008; 48: 449-457Crossref PubMed Scopus (482) Google Scholar], which might have an additive/synergistic role in promoting greater severity of COVID-19. It is conceivable that the secretion of hepatokines for example, reduced adiponectin or the altered secretion of inflammatory lipid mediators in obese patients with MAFLD [15Chen F. Esmaili S. Rogers G.B. Bugianesi E. Petta S. Marchesini G. et al.Lean NAFLD: a distinct entity shaped by differential metabolic adaptation.Hepatology. 2019; 71: 1213-1227Crossref Scopus (218) Google Scholar], may also contribute to the current observations. While this is the first multi-center study to investigate obesity as a possible risk factor for severe COVID-19 illness in patients with MAFLD, some limitations should be recognized. Patients included in our study did not undergo liver biopsy, thus COVID-19 severity in relation to liver histology could not be assessed. Waist circumference, a risk factor for MAFLD, was not measured in our patients, which precluded adjustment of this confounder. In addition, patients were of Asian ethnicity and thus the applicability of the results to other ethnic groups is uncertain. Additional studies will be needed to confirm these findings and to better understand the underlying mechanisms for why the association with obesity is greater in those with MAFLD. In conclusion, our data demonstrate that the risk of obesity to COVID-19 severity is greater in those with, than those without MAFLD. The following is the supplementary data related to this article. All authors declare no conflict of interests.