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NAFLD was independently associated with severe COVID-19 among younger patients rather than older patients: A meta-analysis

Published:October 25, 2022DOI:https://doi.org/10.1016/j.jhep.2022.10.009

      Keywords

      To the Editor,

      Author contributions

      Haiyan Yang and Guangcai Duan conceptualized the study. Ying Wang and Yadong Wang performed literature search and data extraction. Ying Wang and Yadong Wang analyzed the data. Ying Wang and Haiyan Yang wrote the manuscript. All the authors approved the final manuscript.

      Competing interests

      All authors report that they have no potential conflicts of interest.

      Data availability statement

      The data that support the findings of this study are included in this article and available from the corresponding author upon reasonable request.
      In the Journal of Hepatology, Ji et al reported that the presence of non-alcoholic fatty liver disease (NAFLD) was significantly associated with an increased risk for the progression of coronavirus disease 2019 (COVID-19) in multivariate model
      • 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.
      , however, Marjot et al
      • Marjot T.
      • Buescher G.
      • Sebode M.
      • Barnes E.
      • Barritt ASt
      • Armstrong M.J.
      • et al.
      SARS-CoV-2 infection in patients with autoimmune hepatitis.
      and Mushtaq et al
      • Mushtaq K.
      • Khan M.U.
      • Iqbal F.
      • Alsoub D.H.
      • Chaudhry H.S.
      • Ata F.
      • et al.
      NAFLD is a predictor of liver injury in COVID-19 hospitalized patients but not of mortality, disease severity on the presentation or progression - The debate continues.
      reported opposite findings that the presence of NAFLD was not significantly associated with COVID-19 mortality, disease severity or disease progression in multivariate model. This suggests whether the presence of NAFLD was an independent predictor for severe COVID-19 is still inconclusive. The EASL position in Marjot et al’s paper noted that patients with NAFLD were at increased risk for developing severe COVID-19 which might be attributed to the presence of other high-risk comorbidities
      • Marjot T.
      • Eberhardt C.S.
      • Boettler T.
      • Belli L.S.
      • Berenguer M.
      • Buti M.
      • et al.
      Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper.
      . Taken together, we conducted this meta-analysis of risk factors-adjusted effect sizes to determine whether the presence of NAFLD was significantly independently associated with more severe COVID-19.
      This meta-analysis was performed in accordance with the preferred reporting item for systematic reviews and meta-analysis (PRISMA) guidelines
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gøtzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      . The literature was searched in the online databases of Web of Science, PubMed, Elsevier ScienceDirect, Wiley Library, EMBASE, Springer Link, Scopus and Cochrane Library for potentially eligible articles which were published between December 10, 2019 and September 7, 2022. The keywords were used: (“NAFLD” OR “non-alcoholic fatty liver disease” OR “MAFLD” OR “metabolic associated fatty liver disease”) and (“2019-nCoV” OR “SARS-CoV-2” OR “COVID-19” OR “2019 novel coronavirus” OR “severe acute respiratory syndrome coronavirus 2” OR “coronavirus disease 2019”). The exposure group was COVID-19 patients with NAFLD and the control group was COVID-19 patients without NAFLD. The outcome of interest was severe COVID-19 (which was reported as severe/critical illness, severity/progression, intensive care unit (ICU) admission, need for invasive mechanical ventilation (IMV) and mortality, etc. in the original articles). We included all peer-reviewed articles in English providing the risk factors-adjusted effect sizes of the association between NAFLD and severe COVID-19 by multivariate model. We excluded case reports, reviews, preprints, study protocol, editorial, commentary, errata, and studies with un-adjusted effect sizes or without available data. Two independent researchers conducted literature retrieval and data extraction. Any disagreements were settled by discussion between the researchers until the consensus was achieved. In order to find additional pertinent studies, the listed references of the included studies and relevant reviews were further scanned and manually retrieved.
      The Stata 11.2 software was used for statistical analyses. The pooled odds ratio (OR) and 95% confidence interval (CI) were estimated by a random-effects model
      • Greenland S.
      Quantitative methods in the review of epidemiologic literature.
      . The Cochran’s Q test and I2 test were applied to assess statistical heterogeneity. A leave-one-out sensitivity analysis was utilized to evaluate the influences of individual studies on the overall results. Publication bias was assessed by Egger’s test
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      and Begg’s test
      • Begg C.B.
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias.
      . Subgroup analysis was conducted by age (mean/median), male proportion and study design. Probability value less than 0.05 was deemed statistically significant.
      A total of eighteen eligible studies with 22,056 cases were included in this meta-analysis. Our results indicated the presence of NAFLD was significantly independently associated with more severe COVID-19 based on risk factors-adjusted effect sizes (pooled OR = 1.76, 95% CI: 1.24-2.49, Figure 1A). Subgroup analyses by male proportion (pooled OR = 1.64, 95% CI: 1.18-2.26 for ≥ 50% and 2.25, 95% CI: 1.21-4.17 for < 50%) and study design (pooled OR = 1.87, 95% CI: 1.22-2.88 for retrospective studies and 1.40, 95% CI: 1.15-1.70 for the others) yielded consistent results. Subgroup analysis by age (mean/median) showed the presence of NAFLD was significantly independently associated with more severe COVID-19 among younger patients (pooled OR = 2.08, 95% CI: 1.33-3.27 for < 60 years, Figure 1B), but not among older patients (pooled OR = 1.37, 95% CI: 0.97-1.93 for ≥ 60 years, Figure 1C). Sensitivity analysis exhibited deleting each individual study once had no significant impacts on the overall results (Figure 1D, 1E and 1F). Egger’s test (P = 0.003) and Begg’s test (P = 0.005) demonstrated publication bias might exist presently.
      Figure thumbnail gr1
      Figure 1Forest plot demonstrated that the presence of non-alcoholic fatty liver disease (NAFLD) was significantly independently associated with more severe coronavirus disease 2019 (COVID-19) on the basis of eighteen eligible articles reporting risk factors-adjusted effect sizes (A). Subgroup analysis by age (mean/median) showed that the presence of NAFLD was significantly independently associated with more severe COVID-19 among younger patients (< 60 years) (B), but not among older patients (≥ 60 years) (C). Leave-one-out sensitivity analysis exhibited that omitting any single study once had no significant impacts on the overall results (D for total studies, E for < 60 years, and F for ≥ 60 years). * indicates combined effect sizes were calculated from subgroups. # indicates that the study used the hazard ratio (HR) to assess the effect size. The publication bias may favour the publication of positive studies which leads to an overestimation of the positive association between NAFLD and severe COVID-19 and affects the validity and generalisation of the conclusion.
      Although the pooled OR was calculated on the basis of the risk factors-adjusted effects sizes (mainly adjusting age, sex, smoking, obesity, diabetes and hypertension), other factors (such as SARS-CoV-2 variants, status of vaccination and medication)
      • Cornberg M.
      • Eberhardt C.S.
      Protected or not protected, that is the question - First data on COVID-19 vaccine responses in patients with NAFLD and liver transplant recipients.
      ,
      • Cornberg M.
      • Buti M.
      • Eberhardt C.S.
      • Grossi P.A.
      • Shouval D.
      EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients.
      might certainly play an important role in modifying the association between NAFLD and severe COVID-19. Unfortunately, few included studies provided the information of SARS-CoV-2 variants, status of vaccination and medication. We could not assess the impacts of SARS-CoV-2 variants, status of vaccination and medication on the association between NAFLD and severe COVID-19 presently, which should be addressed in the future when more data are available.
      In conclusion, this meta-analysis of risk factors-adjusted effect sizes indicated the presence of NAFLD was significantly independently associated with more severe COVID-19 among younger patients rather than older patients. Future well-designed studies with comprehensive measurements of potential confounding factors are warranted to verify our findings.

      Acknowledgements

      We would like to thank Jie Xu, Jiahao Ren, Li Shi, Mengke Hu, Shuwen Li, Xueya Han, Ruiying Zhang, Jian Wu, Hongjie Hou, Peihua Zhang, Yang Li, Wenwei Xiao and Xuan Liang (All are from Department of Epidemiology, School of Public Health, Zhengzhou University) for their kind help in searching articles and collecting data.

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