COVID-19 infection and liver injury: Clinical features, biomarkers, potential mechanisms, treatment, and management challenges

Table 1 Medications used in the treatment of coronavirus disease 2019 and liver-related complications

Agent	Pharmaceutical property	Mechanism of action	Molecular effects on the liver	Molecular effects on lung	Approved indication(s)	Ref.
Tocilizumab	IL-6 receptor-blocking agent	Reduced the expression of TNF-α and IL-10, downregulated inflammasome activation, and inhibited monocyte phagocytic activity, thereby suppressing the cytokine storm	Mild-to-moderate elevation in transaminases and drug-induced liver injury	Reduced the inflammation of lung tissue	Clinical trial stage	[110,141,142]
Remdesivir	Antiviral drug	RNA-dependent RNA polymerase inhibitor (Adenosine analog)	Transaminases↑ Bilirubin↑	Virus lung titers↓, lung hemorrhage↓, and improved pulmonary function	Approved to treat COVID-19	[126,143]
Oseltamivir	Antiviral drug	Neuraminidase inhibitor; inhibits the release of progeny virus from infected host cells	Transaminases↑ Bilirubin↑(Rare)	Interleukin IL-1β↓, TNF-α↓, IL-4↓, IFN-γ↓	Approved for Influenza A and B	[144,145]
Umifenovir (Arbidol)	Antiviral drug	Spike protein/ACE2 membrane fusion inhibitor; inhibits viral entry into target cells and stimulates the immune response	Transaminase↑	Viral attachment to ACE2↓	Clinical trial stage	[146]
Lopinavir-Ritonavir	Antiviral drug	Antiretroviral protease inhibitor; disruption of viral entry	Golgi fragmentation↑, organelle stress response↑, hepatic injury↑	p53 DNA damage response activation↑	Approved for treatment of HIV	[147-149]
Bicyclol	Antiviral compound candidate	Directly interacts with viral membranes and minimizes the host’s inflammatory response	Transaminases↓, hepatic triglyceride↓	Attenuates LPS- acute lung injury	Approved for treatment of liver injury	[150,151]
Ribavirin (plus IFN-α)	Antiviral drug	Inhibits viral RNA-dependent RNA polymerase (Guanine analog)	Transaminase↓, liver histological damage↓, liver inflammation↓	Improved survival in patients with severe MERS-CoV infection	Approved for some viral diseases including hepatitis C, has limited value in treatment of COVID-19	[152,153]
Favipiravir	Antiviral drug	RNA-dependent RNA polymerase inhibitor	Abnormal liver function test (transaminase↑)	Viral load in the lungs↓, pulmonary tissue inflammation ↓	Approved in some countries to treat influenza, Ebola, and noroviruses	[154,155]
Chloroquine and hydroxychloroquine	Antimalarial medication	Inhibits viral fusion and entry into the cell	IL-6↓, TNF-α↓, NF-kB expression↓, liver tissue apoptosis↓ liver inflammation↓	Lung inflammation↓, oxidative stress↓, pulmonary tissue fibrosis↓	FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19	[156-158]
Probiotics	Live microorganisms	Preventive effects on bacterial and viral infection	Hepatic inflammation↓, transaminases↓, TNF-α↓, ameliorating liver injury and improve liver function	Suppress lung inflammation, preventing effects on acute respiratory tract infections	Approved as dietary supplements	[159-161]
N-Acetyl-Cysteine	Antioxidant agent	Precursor of reduced glutathione and mucolytic agent	Liver lactate↓, improve liver function	Inhibition of ACE activity, inhibit virus replication, pulmonary inflammation↓	Approved for use in humans	[162,163]
Glycyrrhizic acid	Natural triterpenoid saponin isolated from Glycyrrhiza spp	Anti-inflammatory, antioxidative, antiviral compound	Oxidative stress↓, apoptosis↓ in the liver tissue	Inhibited the replication and penetration into cells of the SARS-associated coronavirus, IL-33↓	Approved as a food additive	[164,165]
Vitamin E	Fat-soluble vitamin (alpha-tocopherol)	Antioxidant and immunomodulatory agent	ROS↓, GSH↑, NF-κB activation ↓, inflammation↓, fibrosis↓, transaminase↓	Oxidative stress↓, NO and COX activity↓, T cell proliferation↑	Approved as dietary supplements	[9,166,167]
Vitamin A	Fat-soluble vitamin (all-trans-retinol)	Antioxidant and immunomodulatory agent	Transaminase↓, IL-10↑, NF-κb activation ↓, TNF-α↓	IL1-β↓, Oxidative stress↓, improved pulmonary function	Approved as dietary supplements	[165,166]
Vitamin D	Fat-soluble secosteroids (cholecalciferol)	Reduced viral entry and replication, attenuated inflammation	Modulated liver inflammation and fibrogenesis	TNF-α↓, IFNγ↓, GSH↑, improved pulmonary function	Approved as dietary supplements	[166,168,169]
Vitamin C	Water-soluble vitamin (Ascorbic acid)	Cofactor for a number of enzymatic reactions; antioxidant	Transaminase↓, SOD↑, GSH↑, oxidative stress↓, TNF-α↓	TNFα↓, IL-1β ↓, IL-8↓, NF-κB activation↓, inflammation↓	Approved as dietary supplements	[166,170]
Zinc	Dietary mineral	Anti-inflammatory and antioxidant micronutrient	Decreased pro-inflammatory cytokine production, oxidative stress↓, hepatic tissue apoptosis↓,	Attenuated lung tissue inflammation, TNF-α↓, IL-6↓, IL-1β↓, interferon-γ↑, IL-2↑	Approved as dietary supplements	[171,172]
Mg	Dietary mineral	Anti-inflammatory and antioxidant micronutrient	Liver fibrosis↓, IL-6↓, TNF-α↓, inhibited the NF-κB pathway, transaminase↓	IL-6↓, IL-1β↓, NF-κB activation↓, COX-2 activity↓, prostaglandin E2↓, lung tissue oxidative stress↓	Approved as dietary supplements	[173,174]
Copper	Dietary mineral	Antiviral activity through damage in virus envelope and surface spikes and destruction of the viral genomes	Ceruloplasmin↑, inflammation↓, IL-6↓, oxidative stress↑	Viral replication↓, virus particles released from infected cells↓, viral entry↓	Approved as dietary supplements	[175,176]
Dexamethasone	Corticosteroid medication	Reduced aggressive inflammatory response	VLDL↑, HDL↑, IL-1β↓, IL-2↓, TNF-α↓, interferon-γ↓, prostaglandins production↓, liver inflammation↓, prevented the liver fibrosis	Pulmonary inflammation↓, NF-κB activity↓, oxidative markers↓, lung tissue fibrosis↓, mortality in patients with severe COVID-19 disease↓	WHO-approved treatment for COVID-19	[177,178]

ACE: Angiotensin-converting enzyme; COVID-19: Coronavirus disease 2019; COX-2: Cyclooxygenase-2; DNA: Deoxyribonucleic acid; FDA: Food and Drug Administration; GSH: Glutathione; HDL: High density lipoprotein. HIV: Human immunodeficiency virus; IFN-γ: Interferon-gamma; IL-6: Interleukin 6; MERS-CoV: Middle East respiratory syndrome -coronavirus; NF-ΚbB: Nuclear factor kappa-light-chain-enhancer of activated B cells NF-kappa B; RNA: Ribonucleic acid; ROS: Reactive oxygen species; SOD: Superoxide dismutase; TNF-α: Tumor necrosis factor-α; VLDL: Very low-density lipoprotein.