Association of COVID-19 with hepatic metabolic dysfunction

Table 1 Metabolic alterations in coronavirus disease 2019 with implications

Metabolite alteration	Implications/association
Increased branched chain amino-acids	Insulin resistance, reactive oxygen species production, and pro-inflammatory responses
Decreased tryptophan; Increased kynurenine	Increased kynurenine tryptophan ratio indicates inflammatory response
Increased glutamic acid; Decreased glutamine	Lower glutamine level is associated with insulin resistance and an increased risk of diabetes
Decrease arginine; Increased ornithine	Attempt to suppress virus-specific CD8+ T cell. Delayed interferon response or metabolic syndrome tend to increase arginine/ornithine ratio, causing tissues damage
Increased spermidine and spermine	Help structural assembling and genome replication
Increased serum triglycerides and VLDL; Decreased total cholesterol, HDL and LDL; Upregulation of fatty acid synthesis	Viral replication, inflammation, atherogenic risk, hepatic steatosis
Increased ketone bodies and 2-hydroxybutyric acid	Altered energy metabolism and oxidative stress
Decreased glycerophospholipid; Increased lysophospholipids	Indicates inflammation and tissue damage
increased levels of pyruvate, pyruvate kinase and lactate dehydrogenase	Indicates enhanced glucose metabolism. Increased glycolysis promotes replication of SARS-CoV-2 and cytokine storm
Increased methionine sulfoxide levels; Decreased glutathione levels	Indicative of increased oxidative stress

HDL: High-density lipoprotein; LDL: Low-density lipoprotein; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; VLDL: Very-low-density lipoprotein.

Table 2 Meta-analyses of associations between coronavirus disease 2019 and metabolic diseases

Ref.	Metabolic condition	COVID-19 (N); Studies/Patients	Main results
Ho et al[91]	Obesity	61/270241	Obesity was associated with more severe disease (OR 3.13, 95%CI: 1.41-6.92) and mortality (OR 1.36, 95%CI: 1.09-1.69)
Yang et al[92]	Obesity	50/18 260 378	Obesity was associated with a higher risk of SARS-CoV2 infection (OR: 1.39, 95%CI: 1.25-1.54), increased disease severity (OR: 3.74, 95%CI: 1.18-11.87) and mortality (OR: 1.65, 95%CI: 1.21-2.25)
Huang et al[2]	DM	30/6452	DM was associated with composite poor outcome (RR 2.38 [1.88, 3.03], P < 0.001)
Kumar et al[59]	DM	33/16003	The combined corrected pooled OR of mortality or severity was 2.16 (95%CI: 1.74-2.68; P < 0.01)
Atmosudigdo et al[94]	Dyslipidemia	09/3663	Dyslipidemia was associated with poor outcome (RR 1.39 [1.02, 1.88], more so in patients with older age, male, and hypertension
Hariyanto et al[95]	Dyslipidemia	07/6922	Dyslipidemia was associated with severe disease (RR 1.39 (95%CI: 1.03-1.87)
Du et al[93]	Hypertension	24/99918	Patients with hypertension had a 1.82-fold higher risk for critical COVID-19 (OR: 1.82; 95%CI: 1.19-2.77; P = 0.005) and a 2.17-fold higher risk for COVID-19 mortality (OR: 2.17; 95% CI: 1.67-2.82; P < 0.001)
Zuin et al[4]	Metabolic syndrome	06/209.569	Pre-existing metabolic syndrome was associated with higher risk of mortality (OR: 2.30, 95%CI: 1.52-3.45). Meta-regression showed a direct correlation with hypertension, DM and hyperlipidaemia
Tao et al[5]	MAFLD	07/2141	MAFLD increased the risk of severe COVID-19 (OR: 1.80, 95%Cl: 1.53-2.13)
Pan et al[96]	MAFLD	06/1293	MAFLD increased the risk of disease severity, with a pooled OR of 2.93 (95%CI: 1.87, 4.60)

COVID-19: Coronavirus disease 2019; CI: Confidence interval; DM: Diabetes mellitus; RR: Relative risk, OR: Odds ratio; MAFLD: Metabolic associated fatty liver disease.