Metabolic associated fatty liver disease increases the severity of COVID-19: A meta-analysis.

BACKGROUND: The association between metabolic-associated fatty liver disease (MAFLD) and disease progression in patients with the coronavirus disease 2019 (COVID-19) are unclear. AIMS: To explore the association between MAFLD and the severity of COVID-19 by meta-analysis.
METHODS: We conducted a literature search using PubMed, EMBASE, Medline (OVID), and MedRxiv from inception to July 6, 2020. Newcastle-Ottawa Scale (NOS) and Stata 14.0 were used for quality assessment of included studies as well as for performing a pooled analysis.
RESULTS: A total of 6 studies with 1,293 participants were included after screening. Four studies reported the prevalence of MAFLD patients with COVID-19, with a pooled prevalence of 0.31 for MAFLD (95CI 0.28, 0.35, I2 = 38.8%, P = 0.179). MAFLD increased the risk of COVID-19 disease severity, with a pooled OR of 2.93 (95CI 1.87, 4.60, I2 = 34.3%, P = 0.166).
CONCLUSION: In this meta-analysis, we found that a high percentage of patients with COVID-19 had MAFLD. Meanwhile, MAFLD increased the risk of disease progression among patients with COVID-19. Thus, better intensive care and monitoring are needed for MAFLD patients infected by SARS-COV-2.

Introduction

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 23 million confirmed cases and 800 thousand deaths worldwide as of August 24, 2020 (https://covid19.who.int/). Emerging data suggest that hypertension, diabetes, and cardiovascular diseases (CVDs) are highly prevalent among patients hospitalized with COVID-19, and that these may be associated with an increased risk of mortality due to the virus. Metabolic associated fatty liver disease (MAFLD) is a well-known risk factor for CVDs and diabetes, and has been closely related to mortality due to these diseases [1,2]. MAFLD was reported to affect approximately 20–30% of people worldwide [3], [4], [5]. Several studies demonstrated that MAFLD could increase disease severity in patients with COVID-19. However, Zhou et al. found that MAFLD was not significantly associated with a higher risk of disease severity in young patients [6]. Therefore, in order to clarify the role of MAFLD among patients with COVID-19, we conducted a meta-analysis to summarize the existing evidence about the pooled prevalence of MAFLD, as well as the association between MAFLD and disease severity among patients with COVID-19.

Methods

Search strategy

We conducted a literature search using PubMed, EMBASE, Medline(OVID), and MedRxiv from inception to July 6, 2020. We used keywords and MeSH terms to retrieve potential suitable papers, including “SARS-COV-2”, “COVID-19”, “metabolic associated fatty liver disease”, “nonalcoholic fatty liver disease (NAFLD)”, and “nonalcoholic steatohepatitis (NASH)”. The detail of the search strategy used is shown in the Supplementary information.

Study selection

We screened the titles and abstracts of papers. For potential eligible papers, we obtained the full text. The progression of screening was determined independently by (Pan Lu and Xia Xie). Disagreements were resolved through further discussions or third-party arbitration.

Eligibility criteria

We included studies investigating the association between MAFLD and disease severity among patients with COVID-19. We excluded studies when it was a review or if the study was not in English. MAFLD was defined by criteria based on hepatic steatosis, in addition to meeting one of the following clinical parameters, such as being overweight, having type 2 diabetes mellitus, or exhibiting metabolic dysregulation [5,7]. All of studies evaluated the severity of COVID-19 according to the criteria in Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). Patients were regarded as severe cases when they meet any of following conditions: (i)significantly increased respiration rate; (ii)hypoxia; (iii)consciousness disorders: apathy, somnolence, coma, and convulsions; (iv)food refusal or feeding difficulty and dehydration; (v)other manifestations: such as bleeding and coagulation disorders, myocardial damage, gastrointestinal dysfunction, raised level of liver enzyme, and rhabdomyolysis; (vi)critical cases [8].

Data extraction

Two authors (Xia Xie and Jiang Yuan) independently extracted the following information from the included studies: country, investigation time, age, study design, sample number, percentage of males, and prevalence of MAFLD.

Quality assessment of the included studies

Study quality was independently performed by (Jiachen Xu and Dawei Guo) using the Newcastle-Ottawa Scale (NOS). The NOS scale for cross-sectional studies includes selection, comparability, and outcome. A high score indicates a high quality.

Statistical analysis

We performed pooled analysis using Stata 14.0 (Stata Corp, College Station, TX). A fixed effects model was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for the association between MAFLD and disease severity among patients with COVID-19. Heterogeneity was examined using the I value and Cochran's Q test. A lower I value indicated lower heterogeneity. We also calculated the pooled prevalence of MAFLD among patients with COVID-19.

Results

Included studies

A total of 6 studies with 1293 participants were included after screening (Fig. 1 ) [1,6,[9], [10], [11], [12]. All of these studies were performed in China, and included four cross-sectional studies and two case-control studies (Table 1 ). All studies evaluated the severity of COVID-19 according to the criteria listed in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). The NOS score ranged from 8 to 9 (Table S1–2).

Fig. 1

The flowchart of research screening.

Table 1

The characteristics of the included studies.

Study	Region	Age	Sample	Study design	Male	MAFLD%	NOS score
Zhou Y(a) 2020	China	–	327	cross-sectional study	–	28.4%	9
Zhou YJ(b) 2020	China	42.1 ± 11.4	101	case-control study	0.745	–	8
Targher G 2020	China	47	310	cross-sectional study	0.481	30.3%	8
Ji D 2020	China	44.5(34.8–54.1)	202	cross-sectional study	0.559	37.6%	9
Zheng K 2020	China	47	214	cross-sectional study	0.258	30.8%	8
Gao F 2020	China	46.0 ± 13.0	130	case-control study	0.631	–	9

Abbreviations:NOS, Newcastle-Ottawa Scale; MAFLD, Metabolic associated fatty liver disease;.

The pooled prevalence of MALFD among patients with COVID-19

Four studies reported the prevalence of MAFLD patients with COVID-19, with pooled prevalence of MAFLD found to be 0.31(95CI 0.28, 0.35, I=38.8%, P = 0.179) (Fig. 2 ).

Fig. 2

The pooled prevalence of MAFLD among patients with COVID-19.

MALFD increases the risk of disease severity among patients with COVID-19

Six studies investigated the association between MAFLD and disease severity risk in patients with COVID-19. MAFLD increased the risk of COVID-19 disease severity, with a pooled OR of 2.93 (95CI 1.87, 4.60, I=34.3%, P = 0.166) (Fig. 3 ).

Fig. 3

The association of MAFLD with disease severity among patients with COVID-19.

Discussion

In the present study, patients with COVID-19 had high percentage of MAFLD, with MAFLD found to increase the risk of disease progression in patients with COVID-19. MAFLD was defined by criteria based on hepatic steatosis, in addition to metabolic diseases, these studies had a high percentage among patients with COVID-19. For instance, Richardson et al. reported a prevalence of 41.7% for obesity and 33.8% for diabetes among 5700 patients with COVID-19 in New York [13]. Meanwhile, metabolic diseases were significantly associated with adverse clinical outcomes in patients with COVID-19 [14], [15], [16]. Recently, several meta-analyses demonstrated that diabetes and obesity were associated with increased risk for mortality and disease severity of COVID-19 [17,18].

For COVID-19 infection to occur, SARS-CoV-2 must bind to the host cell surface's ACE2 receptor, which initiates the host defense response and disease process [19,20]. The expression of ACE2 was higher in the animal model of hepatic steatosis [21], which may increase the risk of SARS-CoV-2 entry into the hepatocytes, thus leading to liver injury. Meanwhile, liver injury was reported to be significantly associated with an increased risk of mortality among patients with COVID-19 [22], [23], [24]. In addition, patients with MAFLD were characterized by impaired hepatic innate immunity, such as having macrophage in polarization stages, as well as exhibiting increased levels of inflammatory mediators and cytokines [25,26]. Therefore, the status of inflammation associated with MAFLD further exacerbates the infection in patients with COVID-19 and can even lead to a cytokine storm, which greatly increases mortality risk.

There are several limitations in our present study. First, the sample number included studies which were small and conducted only in China, which may have affected the extrapolation of the results. Fortunately, we conducted retrieval of systematic references using several open databases and medRxiv. However, the results still need to be further validated using large-scale studies involving a variety of regions and races. Second, there were only six studies included in our final analysis, with only one study having a sub-group analysis, which may have impacted our pooled results. Nevertheless, the heterogeneity of the studies was reasonably acceptable, thus ensuring the reliability of outcomes in the studies. Finally, the included studies were cross-sectional studies and case-control studies, which are considered to be inferior to prospective cohort studies.

In conclusion, patients with COVID-19 had high percentage of MAFLD. In addition, MAFLD increased the risk of disease progression in patients with COVID-19. Thus, better intensive care and monitoring are needed for MAFLD patients infected by SARS-COV-2.

Sources of funding, grant support

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Financial disclosure

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Declaration of Competing Interest

No potential conflicts of interest were disclosed.