Table 1 summarizes the clinical and biological characteristics on admission for patients with mild and moderate disease.

LFT laboratory data showed higher elevations of AST (p<0.001), ALT (p=0.05), and GGT (p=0.004) in addition to lower albumin (p<0.001) and PT (p=0.042) in patients with moderate versus mild COVID-19 (Table 1). AST levels were higher in patients hospitalized in a CHU compared to those in ER: 1-2xULN (p=0.001) and >2xULN (p=0.001).

Patients with moderate COVID-19 exhibited elevated GGT levels compared to mild disease, 53.6% vs 16.7% (p=0.016) respectively and more disturbed hepatocellular (p=0.002), cholestatic (p=0.004) and mixed-type (0.004) patterns. These patients had also higher NFS (p<0.001) and more severe liver fibrosis than patients with mild COVID-19: 71.7% had an intermediate/high FIB-4 fibrosis score compared to 41.6% with mild disease (p<0.001). Patients with moderate disease had more NAFLD with an intermediate/high FIB-4 score compared to patients with mild disease (p<0.001) (Table 1).

As can be seen in Table 2, after adjusting for confounding factors that could disturb LFTs, such as hypoxemia and hepatotoxic drugs, patients with AST 2xULN and hepatocellular pattern 2xULN had a 5.5-fold higher risk of being hospitalized (OR 5.599; 95% CI: 1.29–24.25, p=0.021 and OR 5.499; 95%CI: 1.27–23.86; p=0.023, respectively). Patients with metabolic syndrome (the association of 3 metabolic risk factors (MRF)) had more than 2.5-fold higher risk of hospitalization (OR 2.56; 95%CI: 1.292–5.09, p=0.007).

Moderate disease was associated with an intermediate (OR 2.405; 95%CI: 1.39–4.15; p=0.002) and high (OR 5.415; 95%CI: 2.69–10.89; p< 0.001) FIB-4 score. Similarly, patients with an elevated NFS had a higher risk of hospitalization (OR 1.754 95%CI: 1.27–2.43; p<0.001).

In multivariate analyses, patients with metabolic syndrome had almost a 2.4-fold risk of being hospitalized (OR 2.37; 95% CI: 1.18–4.75, p=0.015).

## Comparison between mild/moderate and severe COVID-19

We compared the clinical and laboratory tests and radiological findings in patients with severe versus those with moderate and mild COVID-19 disease (Table 3).
The laboratory liver tests showed more elevated AST (p<0.001), ALT (p=0.002), and TBIL levels (p=0.01), in addition to lower albumin (p<0.001) and PT (p<0.001) in severe disease patients (Table 3).

Concerning abnormal LFT patterns, severe COVID-19 was associated with all types of patterns: hepatocellular (p<0.001), cholestatic (p=0.028), and mixed (p<0.001).

In severe disease patients, 89.3% had intermediate and high FIB-4 scores compared to 65.5% of patients with moderate and mild disease (p<0.001). More patients with severe COVID-19 had NAFLD associated with a high FIB-4: 72.8% vs. 57.9%, respectively (p<0.001) (Table 3).

After adjusting for confounding factors, as described, abnormal LFTs at admission such as AST>2x ULN (OR 3.187; 1.99-5.08; p< 0.001), hepatocellular pattern >2x ULN (2.265; 95% CI 1.48-3.45; p< 0.001), intermediate and high FIB-4 score (OR 2.006; 95%CI 1.09-3.67; p=0.024 and OR 4.756; 95%CI: 2.68-8.43; p<0.001 respectively) or metabolic syndrome (OR 2.45, 95%CI1.07-5.61, p=0.03) were associated with a worse evolution of the disease (Table 4).

In multivariate analyses, patients with high FIB-4 index had 3-fold risk to develop a severe disease (OR 3.11; 95%CI 1.4-6.91, p=0.005).

## Discussion

Coronavirus disease 2019, the pandemic caused by SARS-CoV-2, has been associated with substantial morbidity and mortality (15). More information concerning SARS-CoV-2 infection is needed to rapidly identify patients likely to develop severe disease, requiring adjusted care. This is the first monocentric study that describes the outcome of a large cohort of COVID-19 patients based on clinical, laboratory, and radiological data collected at admission, enabling us to rapidly identify factors associated with outcomes that predict mild, moderate, or severe disease at the time of hospital admission the hospital.

Recently published studies have shown that patients admitted for COVID-19 often present with abnormal liver test, the incidence of liver injury ranging from 14% to 78% (1, 6, 16). Moreover, preexisting liver disease has been shown to be associated with worsening infection prognosis (17). However, the mechanistic events remain to be determined, and the
causes of LFTs may be multifactorial, including causes unrelated to COVID-19. In contrast to previous studies, we analyzed only the laboratory liver tests at baseline in order to avoid the anomalies induced by different drugs administrated during the hospitalization.

In this present cohort, on admission, abnormal LFTs were present in 68.9% of patients, being more elevated than those previously reported in China at 14.9%, yet similar to those estimated in the United States at between 40%–67.5%. This controversy could be explained by the higher proportion of obese and diabetic patients in occidental countries (18).

Hepatocellular parameters, such as the AST and ALT, were elevated in 57% and 35.9% of patients, respectively, being beyond 2xULN in 17.4% and 4%, respectively. Patients with severe disease had a higher AST compared with moderate and mild disease patients (p<0.001). The ALT was also more elevated in severe COVID-19 patients when compared with the other patient groups (p=0.02). After adjusting for confounding factors, elevated transaminases, such as AST >2xULN, and hepatocellular pattern type >2xULN were associated with a 3-fold (p<0.001) and almost 3.5-fold (p<0.001) higher risk, respectively, of a poorer clinical outcome.

Recent studies have shown that SARS-CoV-2 binds angiotensin converting enzyme 2 (ACE2) receptors localized both in the liver and bile duct cells. The expression is higher in the cholangiocytes that may be associated with cholestatic abnormalities (elevated ALP and GGT) rather than hepatocellular abnormalities (AST and ALT) (1, 20).

In our study, the ALP, GGT, and TBIL were elevated in 11.4%, 56.5%, and 5.8% of patients, respectively. Only an abnormal GGT was associated with moderate disease (GGT ULN, OR 0.108; 95%CI: 0.013–0.89, p=0.039). Interestingly, ALP >1–2xULN was more common in moderate and mild disease (91.5%) than in severe disease (83.9%) (p=0.045). Our data confirm the hypothesis of Hundt et al. reporting that the mechanism of liver damage may be not caused by direct cytopathic effects of the novel coronavirus (19).

Obesity was associated with COVID-19 disease severity (21, 22). Indeed, in our study, 72.5% of patients that required hospitalization were overweight, with 34.6% being obese. The proportion of overweight patients increased with disease severity, as follows: 58.4% in mild, 71.8% in moderate, and 73.3% in severe COVID-19. Moreover, the hospitalized patients had a higher BMI compared to those discharged from an ER: 28.9 vs. 26.9Kg/m² (p=0.001).
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A strong association between obesity and the severity of COVID-19 was previously reported, even in the absence of other comorbidities, yet the underlying mechanism is unclear (23).

Obesity is characterized by a chronic inflammatory state and disrupted immune response.
The main cytokines responsible for chronic inflammation are tumor necrosis factor-alpha (TNF-α), interleukin (Il)-6, and IL-1 beta(β) (5). Moreover, SARS-CoV-2 may cause a hyper-inflammatory reaction through the excessive release of cytokines, a condition known as “cytokine storm,” that may be enhanced by obesity, particularly in patients with a preexisting liver disease like NAFLD (24). Adipose tissue may also be a viral reservoir and an immunological hub for the inflammatory response (25). Individuals with severe obesity, diabetes, and hypertension are more likely to be infected and are at a higher risk of complications and death due to COVID-19 (2).

Indeed, in our study, metabolic factors were associated with the severity of COVID-19.
Hypertension (p=0.002) and dyslipidemia (p=0.001) were associated with moderate disease,
and diabetes was associated with a severe course of the disease (p=0.032). Patients with
metabolic syndrome had a 2.5-fold higher risk to develop a moderate (p=0.007) or a severe
disease (p=0.033).

Abnormal GGT is commonly observed in NAFLD and is a sensitive marker of steatosis (11). In our study, the ALP was elevated only in 11.4% of patients, and the mean values were not significantly higher in mild disease compared to moderate (p=0.938) and severe forms (p=0.178). Moreover, 56.5% of patients had abnormal GGT levels, and this was correlated with the severity of COVID-19 when comparing severe versus moderate (p=0.02) and mild disease forms (p=0.016).

The prognosis of liver mortality was related to liver fibrosis (26). Liver fibrosis evaluated with the FIB-4 score was associated with the severity of COVID-19 illness: 71.7% of patients with intermediate/high FIB-4 scores needed hospitalization compared to 41.6% of those with only mild disease (p<0.001), and it was higher in patients with severe SARS-COV-2 infection than in those with moderate and mild disease (89.3% compared to 65.5%, respectively) (p<0.001).

Patients who needed hospitalization had a more elevated NFS compared to those who were discharged from an ER (p=0.001).
We associated the FIB-4 scores in patients diagnosed with NAFLD (Tables 2 and 4). In the hospitalized patients, 84.2% had an intermediate/high FIB-4 compared to 67.3% of those discharged from an ER (p<0.001). In patients with a high FIB-4, 72.8% had severe disease compared to the 57.9% of those with moderate and mild disease (p<0.001). Moreover, the patients with NAFLD without fibrosis (FIB-4<1.3) were at a lower risk of hospitalization (OR 0.404; 95%CI: 0.20-0.81; p<0.011).

In the multivariate-adjusted analysis, patients with high FIB-4 scores had an almost 3-fold greater risk of hospitalization (p=0.011), and a worse course of disease (p<0.001).

In the context of the COVID-19 pandemic, along with the high prevalence of NAFLD in the general population, it is mandatory to early identify patients at risk of developing a severe disease. Applying non-invasive tests such as the FIB-4 and NFS in patients with metabolic liver disease could enable us to better and more quickly identify these patients that may have a poorer prognosis (27).

Our study had some limitations. First, the data were collected retrospectively, and there was missing information regarding the tobacco and alcohol consumption, several clinical parameters (waist and hip circumferences), and laboratory tests pertaining to metabolic syndrome, including glucose, glycated hemoglobin, cholesterol, and triglycerides levels. Second, while all patients underwent transaminase measurements at admission, only half of them underwent cholestasis enzyme assessment at admission, which could be deemed as a limitation in the statistical analysis. Third, HIS index was used in several publications to define NAFLD in COVID 19 patients (8-10). It is a simple, disponible score that may help us to easy identify high-risk patients. His limitation is related to the elevated transaminases levels that could underestimate the index.

In conclusion, obese patients with metabolic syndrome and a preexisting liver disease, including NAFLD and liver fibrosis, display a dysregulated hepatic innate immunity and pro-inflammatory state that is likely to enhance the "cytokine storm" due to SARS CoV-2 infection, leading to severe COVID-19 disease. Thus, abnormal LFTs at admission predict the outcome of COVID-19 patients.

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<caption>Figure 1. Flowchart of patients included in the study</caption>
<figure><img src="image_6.png" /><figcaption>Table 1. Characteristics of patients with mild and moderate COVID-19 on admission</figcaption></figure>
<table><thead><tr><th>Variable</th><th>Mild COVID-19 (n=101)</th><th>Moderate COVID-19 (n=393)</th><th>p-value</th></tr></thead><tbody><tr><td>Age (years, SD*)</td><td>57.7 (18.4)</td><td>65.7 (7)</td><td>&lt;0.001</td></tr><tr><td>Gender (male, %)</td><td>52 (51.4)</td><td>198 (50.4)</td><td>0.468</td></tr><tr><td>BMI (kg/m², SD)</td><td>26.9 (4.9)</td><td>28.8 (5)</td><td>0.004</td></tr><tr><td><strong>Comorbidity</strong></td><td></td><td></td><td></td></tr><tr><td>Diabetes (n, %)</td><td>21 (20.8)</td><td>105 (26.7)</td><td>0.251</td></tr><tr><td>Hypertension (n, %)</td><td>38 (37.6)</td><td>217 (55.2)</td><td>0.002</td></tr><tr><td>Dyslipidemia (n, %)</td><td>17 (16.8)</td><td>129 (32.8)</td><td>0.001</td></tr><tr><td>Chronic pulmonary disease (n, %)</td><td>19 (18.8)</td><td>94 (24)</td><td>0.291</td></tr><tr><td>Chronic cardiac disease (n, %)</td><td>19 (18.8)</td><td>106 (27)</td><td>0.097</td></tr><tr><td>Chronic kidney disease (n, %)</td><td>4 (4)</td><td>26 (6.6)</td><td>0.482</td></tr><tr><td>Cancer (n, %)</td><td>2 (2)</td><td>20 (5.1)</td><td>0.277</td></tr><tr><td><strong>Symptoms onset</strong></td><td></td><td></td><td></td></tr><tr><td>“Flu-like” symptoms (n, %)</td><td>87 (86.1)</td><td>366 (93.1)</td><td>0.041</td></tr><tr><td>Respiratory symptoms (n, %)</td><td>87 (86.1)</td><td>351 (89.3)</td><td>0.014</td></tr><tr><td>Digestive symptoms (n, %)</td><td>40 (39.6)</td><td>208 (52.9)</td><td>0.019</td></tr><tr><td>Neurological symptoms (n, %)</td><td>45 (44.6)</td><td>184 (46.8)</td><td>0.738</td></tr><tr><td><strong>Clinical features</strong></td><td></td><td></td><td></td></tr><tr><td>Oxygen saturation SaO2 (%, SD)</td><td>96 (3.9)</td><td>92.1 (5.9)</td><td>&lt;0.001</td></tr><tr><td>Debit of oxygen at admission (L/mn, sd)</td><td>0.4 (1.8)</td><td>2.3 (7.4)</td><td>&lt;0.001</td></tr><tr><td>Systolic arterial pressure (mmHg, SD)</td><td>132.4 (17.9)</td><td>133.1 (25.8)</td><td>0.683</td></tr><tr><td><strong>Laboratory tests</strong></td><td></td><td></td><td></td></tr><tr><td>AST U/L (reference range 11-34)</td><td>30.4 (20.4)</td><td>45.5 (36.2)</td><td>&lt;0.001</td></tr><tr><td>ALT U/L (reference range 8-41)</td><td>35.7 (27.5)</td><td>42.3 (34)</td><td>0.05</td></tr><tr><td>ALP U/L (reference range 41-117)</td><td>66.1 (13.2)</td><td>76.1 (40.6)</td><td>0.938</td></tr><tr><td>GGT U/L (reference range 6-40)</td><td>30.2 (23.7)</td><td>87.6 (119.2)</td><td>0.004</td></tr><tr><td>Bilirubin µmol/L, (reference range 1.7-21.0)</td><td>9.1 (4.9)</td><td>11.3 (18.3)</td><td>0.279</td></tr><tr><td>Albumin g/L, (reference range 35-50)</td><td>43.1 (3.9)</td><td>39.2 (5)</td><td>&lt;0.001</td></tr><tr><td>Abnormality type (n, %)</td><td></td><td></td><td></td></tr><tr><td>Hepatocellular &gt; ULN</td><td>39 (38.6)</td><td>221 (56.2)</td><td>0.002</td></tr><tr><td>Cholestatic &gt; ULN</td><td>2 (16.7)</td><td>112 (61.2)</td><td>0.004</td></tr><tr><td>Mixed &gt; ULN</td><td>0 (0)</td><td>72 (39.3)</td><td>0.004</td></tr><tr><td>PT (normal range &gt;70%) (%, SD)</td><td>92.6 (8)</td><td>87.9 (15.7)</td><td>0.042</td></tr><tr><td>CRP mg/L (reference range &lt; 4)</td><td>36.1 (54.1)</td><td>87.9 (70.5)</td><td>&lt;0.001</td></tr><tr><td>Leucocytes *10<sup>9</sup>/L (reference range 4.5-6.5)</td><td>6.2 (2.6)</td><td>7(3.4)</td><td>0.02</td></tr><tr><td>Neutrophil count *10<sup>9</sup>/L (reference range 1.3-7.7)</td><td>4.2 (2.2)</td><td>5.3 (3)</td><td>&lt;0.001</td></tr><tr><td>Lymphocytes *10<sup>9</sup>/L (reference range 1.0-4.0)</td><td>1.5 (0.8)</td><td>1.2 (1.3)</td><td>&lt;0.001</td></tr><tr><td>Lymphocytes *10<sup>9</sup>/L ≤1.0 (n, %)</td><td>31 (30.7)</td><td>200 (50.9)</td><td>0.001</td></tr><tr><td>Fibrinogen g/L (reference range: 2-4)</td><td>5(1.4)</td><td>5.9 (1.5)</td><td>0.016</td></tr></tbody></table>
<table><tr><td>Platelets *10<sup>9</sup>/L<br>(reference range: 150-400)</td><td>236.2 (104.6)</td><td>226.3 (99.8)</td><td>0.331</td></tr><tr><td>D-Dimers (reference range: 150-400)</td><td>765 (698)</td><td>2452.9 (4111.5)</td><td>0.05</td></tr><tr><td><strong>Metabolic and fibrosis characteristics</strong></td><td></td><td></td><td></td></tr><tr><td>FIB-4 status (n, %)</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>&lt;1.3</td><td>59 (58.4)</td><td>111 (28.3)</td><td></td></tr><tr><td>1.3-2.67</td><td>29 (28.7)</td><td>142 (36.2)</td><td></td></tr><tr><td>&gt;2.67</td><td>13 (12.9)</td><td>139 (35.5)</td><td></td></tr><tr><td>NAFLD (n, %)</td><td>62 (61.4)</td><td>249 (63.4)</td><td>0.73</td></tr><tr><td>NAFLD+ et FIB-4 (n, %)</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>NAFLD + FIB-4 &lt;1.3</td><td>33 (32.7)</td><td>62 (15.8)</td><td></td></tr><tr><td>NAFLD + FIB-4 1.3-2.67</td><td>19 (18.8)</td><td>94 (23.9)</td><td></td></tr><tr><td>NAFLD + FIB-4 &gt;2.67</td><td>49 (48.5)</td><td>237 (60.3)</td><td></td></tr><tr><td>NFS (mean, SD)</td><td>-2 (1.5)</td><td>-0.7 (1.7)</td><td>&lt;0.001</td></tr><tr><td><strong>Radiologic findings</strong></td><td></td><td></td><td></td></tr><tr><td>Severity of pneumonia (CT scan)</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>-absence</td><td>25 (26%)</td><td>24 (6.8%)</td><td></td></tr><tr><td>-&lt;25%</td><td>58 (60.4%)</td><td>185 (52.6%)</td><td></td></tr><tr><td>25-50%</td><td>10 (10.4%)</td><td>116 (33%)</td><td></td></tr><tr><td>&gt;50%</td><td>3 (3.1%)</td><td>27 (7.7%)</td><td></td></tr><tr><td>Delays from symptom onset to<br>hospitalization (days, SD)</td><td>7.2 (6.8)</td><td>7.6 (6.8)</td><td>0.592</td></tr><tr><td>Time of hospitalization (days, SD)</td><td>1 (0.9)</td><td>10.6 (8.5)</td><td>&lt;0.001</td></tr></table>

BMI: body mass index

SD: standard deviation

COVID-19: coronavirus disease 2019

AST: aspartate aminotransferase

ALT: alanine aminotransferase

ALP: alkaline phosphatase

ULN: upper limit of the normal

GGT: gamma-glutamyl transferase

LFTs: liver function tests

PT: prothrombin time

FIB-4: fibrosis-4

CRP: Creatine-reactive protein

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

CT: computed tomography

HSI: hepatic steatosis index

NAFLD: non-alcoholic fatty liver disease

NFS: NAFLD fibrosis score

SaO2: capillary oxygen saturation

TBIL: total bilirubin
<table><caption>Table 2. Factors associated with moderate COVID-19, after adjusting for confounding factors</caption><thead><tr><td></td><td>OR</td><td>95%CI</td><td>p-value</td></tr></thead><tbody><tr><td>MS (MRF 1+2+3)</td><td>2.85</td><td>1.49-5.45</td><td>0.002</td></tr><tr><td>MS (MRF 1+2+4)</td><td>2.56</td><td>1.29-5.09</td><td>0.007</td></tr><tr><td>MS (MFR 1+3+4)</td><td>3.09</td><td>1.29-6.89</td><td>0.006</td></tr><tr><td>NFS score</td><td>1.754</td><td>1.27-2.43</td><td>&lt;0.001</td></tr><tr><td>FIB-4 (1.3-2.67)</td><td>2.405</td><td>1.39-4.15</td><td>0.002</td></tr><tr><td>FIB-4 &gt;2.67</td><td>5.415</td><td>2.69-10.89</td><td>&lt;0.001</td></tr><tr><td>NAFLD+ and FIB-4&lt;1.30</td><td>0.404</td><td>0.20-0.81</td><td>0.011</td></tr><tr><td>ASTULN</td><td>0.395</td><td>0.23-0.66</td><td>&lt;0.001</td></tr><tr><td>AST&gt;2 ULN</td><td>5.599</td><td>1.29-24.25</td><td>0.021</td></tr><tr><td>Hepatocellular type &gt;2 ULN</td><td>5.499</td><td>1.27-23.86</td><td>0.023</td></tr><tr><td>GGT ULN</td><td>0.108</td><td>0.01-0.89</td><td>0.039</td></tr><tr><td>Cholestatic type &gt;ULN</td><td>11.915</td><td>1.45-98.27</td><td>0.021</td></tr><tr><td>Albumin</td><td>0.805</td><td>0.70-0.92</td><td>0.002</td></tr><tr><td>Neutrophil count</td><td>1.13</td><td>1.02-1.25</td><td>0.023</td></tr><tr><td>Lymphocytes&lt;1000/µL</td><td>2.196</td><td>1.33-3.64</td><td>0.002</td></tr><tr><td>Prothrombin time</td><td>0.963</td><td>0.94-0.99</td><td>0.01</td></tr><tr><td>CRP</td><td>1.017</td><td>1.01-1.02</td><td>&lt;0.001</td></tr><tr><td>CRP &lt;100 mg/L</td><td>0.29</td><td>0.14-0.62</td><td>&lt;0.001</td></tr></tbody></table>

OR: odd ratio; CI: confidence interval; MS: metabolic syndrome, MRF: metabolic risk factors: 1-obesity; 2-diabetes, 3-dyslipidemia, 4-hypertension.

Adjustment for confounding factors that could disturb LFTs, as follows: hypoxemia (SaO2 < 93% related to severe pneumopathy) (16); hepatotoxic drugs (acetaminophen, antibiotics) administrated before hospitalization. Hypotension defined by systolic blood pressure < 90mmHg was not considered because of low case number <10
<table><caption>Table 3. Characteristics of patients with mild and moderate versus severe COVID-19 on admission.</caption><thead><tr><th>Variable</th><th>Mild and Moderate COVID-19 (n=494)</th><th>Severe COVID-19 (n=225)</th><th>p-value</th></tr></thead><tbody><tr><td>Age (years, SD*)</td><td>63.1 (17.5)</td><td>68.3 (16.9)</td><td>&lt;0.001</td></tr><tr><td>Gender (male, %)</td><td>251 (50.8)</td><td>138 (61.3)</td><td>0.94</td></tr><tr><td>BMI (Kg/m²) (mean, SD)</td><td>28.4 (5.9)</td><td>28.9 (5.9)</td><td>0.255</td></tr><tr><td><strong>Comorbidity</strong></td><td></td><td></td><td></td></tr><tr><td>Diabetes (n, %)</td><td>126 (25.5)</td><td>75 (33.3)</td><td>0.032</td></tr><tr><td>Hypertension (n, %)</td><td>255 (51.6)</td><td>131 (58.2)</td><td>0.107</td></tr><tr><td>Dyslipidemia (n, %)</td><td>146 (29.6)</td><td>80 (35.7)</td><td>0.118</td></tr><tr><td>Chronic pulmonary disease (n, %)</td><td>113 (23)</td><td>63 (28)</td><td>0.161</td></tr><tr><td>Chronic cardiac disease (n, %)</td><td>125 (25.3)</td><td>72 (32)</td><td>0.071</td></tr><tr><td>Chronic kidney disease (n, %)</td><td>30 (6.1)</td><td>29 (12.9)</td><td>0.003</td></tr><tr><td>Cancer (n, %)</td><td>22 (4.5)</td><td>10 (4.5)</td><td>1</td></tr><tr><td><strong>Symptoms onset</strong></td><td></td><td></td><td></td></tr><tr><td>“Flu-like” symptoms (n, %)</td><td>453 (91.7)</td><td>210 (93.3)</td><td>0.549</td></tr><tr><td>Respiratory symptoms (n, %)</td><td>438 (88.7)</td><td>208 (92.4)</td><td>0.435</td></tr><tr><td>Digestive symptoms (n, %)</td><td>248 (50.2)</td><td>96 (42.7)</td><td>0.064</td></tr><tr><td>Neurological symptoms (n, %)</td><td>229 (46.4)</td><td>106 (47.1)</td><td>0.872</td></tr><tr><td><strong>Clinical features</strong></td><td></td><td></td><td></td></tr><tr><td>Oxygen saturation SaO2 (%, SD)</td><td>92.9 (5.7)</td><td>85.3 (9.1)</td><td>&lt;0.001</td></tr><tr><td>Debit of oxygen at admission (l/mn, sd)</td><td>1.9 (6.7)</td><td>6.5 (7.7)</td><td>&lt;0.001</td></tr><tr><td>Systolic arterial pressure, mmHg</td><td>132.5 (20.8)</td><td>131.5 (20.9)</td><td>0.375</td></tr><tr><td><strong>Laboratory tests</strong></td><td></td><td></td><td></td></tr><tr><td>AST U/L (reference range, 11-34)</td><td>48 (87.8)</td><td>73.1 (64.6)</td><td>&lt;0.001</td></tr><tr><td>ALT U/L (reference range, 8-41)</td><td>40.9 (32.8)</td><td>57.9 (110)</td><td>0.002</td></tr><tr><td>ALP U/L (reference range, 41-117)</td><td>75.2 (39)</td><td>72.3 (39.4)</td><td>0.178</td></tr><tr><td>GGT U/L (reference range, 6-40)</td><td>84.2 (116.5)</td><td>84.7 (79.6)</td><td>0.087</td></tr><tr><td>Total Bilirubin µmol/l (reference range, 1.7-21.0)</td><td>11.1 (17.5)</td><td>11.6 (6.9)</td><td>0.01</td></tr><tr><td>Conjugated Bilirubin µmol/l (reference range&lt; 4.3)</td><td>3.7 (2.6)</td><td>4.2 (2.4)</td><td>0.055</td></tr><tr><td>Albumin g/, (reference range, 35-50)</td><td>39.7 (5)</td><td>36.4 (5.4)</td><td>&lt;0.001</td></tr><tr><td>PT (normal range &gt;70%) (%, SD)</td><td>88.9 (14.6)</td><td>85.6 (14.7)</td><td>&lt;0.001</td></tr><tr><td><strong>Abnormality type (n, %)</strong></td><td></td><td></td><td></td></tr><tr><td>Hepatocellular &gt;ULN</td><td>260 (52.6)</td><td>178 (79.1)</td><td>&lt;0.001</td></tr><tr><td>Cholestatic &gt;ULN</td><td>114 (58.5)</td><td>81 (71.1)</td><td>0.028</td></tr><tr><td>Mixed type &gt;ULN</td><td>72 (36.9)</td><td>72 (63.7)</td><td>&lt;0.001</td></tr><tr><td>CRP mg/L (reference range&lt; 4)</td><td>77.7 (70.6)</td><td>148.7 (92.6)</td><td>&lt;0.001</td></tr><tr><td>Leucocytes *10<sup>9</sup>/l</td><td>6.9 (3.3)</td><td>8.6 (4.4)</td><td>&lt;0.001</td></tr></tbody></table>
<table><tbody><tr><td>(reference range 4.5-6.5)</td><td></td><td></td><td></td></tr><tr><td>Neutrophil count *10<sup>9</sup>/l<br>(reference range 1.3-7.7)</td><td>5.1 (2.9)</td><td>6.9 (3.9)</td><td>&lt;0.001</td></tr><tr><td>Lymphocytes *10<sup>9</sup>/l<br>(reference range: 1.0-4.0)</td><td>1.2 (1.2)</td><td>1 (1.5)</td><td>&lt;0.001</td></tr><tr><td>Lymphocytes *10<sup>9</sup>/L<br>≤ 1.0 (n, %)</td><td>231 (46.8)</td><td>137 (60.9)</td><td>0.001</td></tr><tr><td>Fibrinogen g/l (reference range 2-4)</td><td>5.8 (1.5)</td><td>6.8 (1.4)</td><td>&lt;0.001</td></tr><tr><td>Platelets *10<sup>9</sup>/L<br>(reference range 150-400)</td><td>228.3 (99.8)</td><td>210.6 (5.4)</td><td>0.028</td></tr><tr><td>D-Dimers (reference range 150-400)</td><td>2302.9 (3956.9)</td><td>2849.6 (4072.5)</td><td>0.001</td></tr><tr><td><strong>Metabolic and fibrosis characteristics</strong></td><td></td><td></td><td></td></tr><tr><td>FIB-4 score (n, %)</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>≤1.3</td><td>170 (34.5)</td><td>24 (10.7)</td><td></td></tr><tr><td>1.3-2.67</td><td>171 (34.7)</td><td>67 (29.9)</td><td></td></tr><tr><td>&gt;2.67</td><td>152 (30.8)</td><td>133 (59.4)</td><td></td></tr><tr><td>NAFLD (n, %)</td><td>311 (63)</td><td>134 (59.8)</td><td>0.455</td></tr><tr><td>NAFLD+ et FIB-4 (n, %)</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>NAFLD + FIB-4 &lt;1.3</td><td>95 (19.2)</td><td>20 (8.9)</td><td></td></tr><tr><td>NAFLD + FIB-4 1.3-2.67</td><td>113 (22.9)</td><td>41 (18.3)</td><td></td></tr><tr><td>NAFLD + FIB-4 &gt;2.67</td><td>286 (57.9)</td><td>163 (72.8)</td><td></td></tr><tr><td>NAFLD fibrosis score (mean, SD)</td><td>-0.8 (1.8)</td><td>-0.6 (1.6)</td><td>0.435</td></tr><tr><td><strong>Radiologic findings</strong></td><td></td><td></td><td></td></tr><tr><td>Severity of pneumonia (CT scan)</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>-absence (n, %)</td><td>49 (10.9%)</td><td>10 (5%)</td><td></td></tr><tr><td>-&lt;25%</td><td>243 (54.2%)</td><td>53 (26.6%)</td><td></td></tr><tr><td>25-50%</td><td>126 (28.1%)</td><td>75 (37.7%)</td><td></td></tr><tr><td>&gt;50%</td><td>30 (6.7%)</td><td>61 (30.7%)</td><td></td></tr><tr><td>Delays from symptoms onset to<br>hospitalization (days, SD)</td><td>6.6 (6.2)</td><td>7.2 (5.3)</td><td>0.062</td></tr><tr><td>Time of hospitalization</td><td>8.7 (8.5)</td><td>19.1 (12.8)</td><td>&lt;0.001</td></tr></tbody></table>

SD, standard deviation

mean values

BMI: body mass index

SD: standard deviation

COVID-19: coronavirus disease 2019

AST: aspartate aminotransferase

ALT: alanine aminotransferase

ALP: alkaline phosphatase

ULN: upper limit of the normal

GGT: gamma-glutamyl transferase

LFTs: liver function tests

PT: prothrombin time
FIB-4: fibrosis-4

CRP: Creatine-reactive protein

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

CT: computed tomography

HSI: hepatic steatosis index

NAFLD: non-alcoholic fatty liver disease

NFS: NAFLD fibrosis score

SaO2: capillary oxygen saturation

TBIL: total bilirubin

<table><caption>Table 4. Factors associated with moderate severe COVID-19 after adjusting for confounding factors.</caption><thead><tr><td></td><td>OR</td><td>95%CI</td><td>p-value</td></tr></thead><tbody><tr><td>MS (MRF 1+2+3+4)</td><td>2.45</td><td>1.07-5.61</td><td>0.033</td></tr><tr><td>NFS</td><td>1.181</td><td>1.01-1.37</td><td>0.033</td></tr><tr><td>FIB-4 (1.3-2.67)</td><td>2.006</td><td>1.09-3.67</td><td>0.024</td></tr><tr><td>FIB-4 > 2.67</td><td>4.756</td><td>2.68-8.43</td><td>&lt;0.001</td></tr><tr><td>AST ULN</td><td>0.406</td><td>0.27-0.61</td><td>&lt;0.001</td></tr><tr><td>AST >2 ULN</td><td>3.187</td><td>1.99-5.08</td><td>&lt;0.001</td></tr><tr><td>ALT ULN</td><td>0.716</td><td>0.48-1.05</td><td>0.09</td></tr><tr><td>Hepatocellular type>ULN</td><td>2.265</td><td>1.48-3.45</td><td>&lt;0.001</td></tr><tr><td>Hepatocellular type >2 ULN</td><td>3.404</td><td>2.12-5.47</td><td>&lt;0.001</td></tr><tr><td>GGT>1-3 ULN</td><td>1.676</td><td>0.97-2.88</td><td>0.062</td></tr><tr><td>Albumin ULN</td><td>0.422</td><td>0.21-0.82</td><td>0.01</td></tr><tr><td>Albumin</td><td>0.871</td><td>0.82-0.92</td><td>&lt;0.001</td></tr><tr><td>Leucocytes count</td><td>1.104</td><td>1.05-1.16</td><td>&lt;0.001</td></tr><tr><td>Neutrophil count</td><td>1.136</td><td>1.07-1.21</td><td>&lt;0.001</td></tr><tr><td>CRP >200 mg/L</td><td>2.785</td><td>1.66-4.66</td><td>&lt;0.001</td></tr><tr><td>CRP <100 mg/L</td><td>0.441</td><td>0.29-0.65</td><td>&lt;0.001</td></tr><tr><td>Fibrinogen</td><td>1.317</td><td>1.05-1.64</td><td>0.015</td></tr><tr><td>Lupus-anticoagulant</td><td>4.453</td><td>1.49-13.23</td><td>0.007</td></tr></tbody></table>

OR: odd ratio; CI: confidence interval; MS: metabolic syndrome, MRF: metabolic risk factors: 1-obesity; 2-diabetes, 3-dyslipidemia, 4-hypertension.

Adjustment for confounding factors that could disturb LFTs, as follows: hypoxemia (SaO2 < 93% related to severe pneumopathy) (16), and hepatotoxic drugs (acetaminophen, antibiotics) administrated before the hospitalization. Hypotension defined by systolic blood pressure <90mmHg was not considered because of the low number of cases <10.
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