Liver injury induced by COVID 19 treatment – what do we know?

Table 1 Clinical evidence of coronavirus disease 2019-mediated impact on various biochemical indexes

Biochemical parameters	Observed range (minimum to maximum)	Inference	Ref.
Hepatobiliary function markers
Alanine aminotransferase	15-107 U/L (7590 U/L for one patient with severe hepatitis)	Elevated serum levels	[8-11]
Aspartate transaminase	15-132 U/L (1445 U/L for one patient with severe hepatitis)	Elevated serum levels	[8-11]
Alkaline phosphate	48-118 U/L	Elevated serum levels	[8,10,11]
Total bilirubin	5.0-33.7 μmol/L	Elevated serum levels	[8-11]
Gamma-glutamyl transferase	15-161 U/L	Elevated in severe cases	[8-11]
Albumin	4-45 g/L	Reduced serum levels	[8-11]
Lactate dehydrogenase	124.8-716 U/L	Elevated serum levels	[8,10,11]
Inflammatory markers
Lymphocytes count	(0.64 × 109)-(1.10 ×0 109)/L	Reduced serum levels	[10]
C-Reactive protein	6.9-88.6 mg/L	Elevated serum levels	[10]
Interleukin-6	28.72 ng/L	Elevated serum levels	[10,33]
CD8+ T cell count	(220 × 107)-(220 × 109) cells/L	Reduced blood levels	[10]
Erythrocyte sedimentation rate	Maximum 58 mm/h	Elevated	[10]
Other markers
D-dimer levels	0.20-4.55 μg/mL	Elevated plasma levels	[32,33]
Fibrinogen levels	220.0-528.0 mg/dL	Elevated plasma levels	[31,33]

Table 2 Clinical evidence of coronavirus disease 2019 drug-induced liver injury

Therapeutic agent	Molecular mechanism against SARS-CoV-2	Impact on liver	Ref.
Antiviral agents
Remdesivir	It inhibits RNA-dependent RNA polymerase of SARS-CoV-2 and hence hinders its replication post infection	Mild-to-moderate increase in serum ALT, AST, and total bilirubin levels	[10,11,13,52,60,83,84]
Lopinavir-Ritonavir	It is a protease inhibitor that disrupts viral replication and its release from host cells	Elevated serum enzyme levels varying from hepatocellular to cholestatic, increased Golgi fragmentation, and organelle stress response leading to hepatic injury	[10,11,13,52,60]
Favipiravir	It inhibits RNA-dependent RNA polymerase of SARS-CoV-2 and hence hinders its replication post infection	Abnormal liver function test (elevated serum ALT, AST, and total bilirubin levels)	[10,11,52,57,60,85]
Oseltamivir	It selectively inhibits viral neuraminidase and alters its release from host cells	Elevated serum ALT levels and total bilirubin levels in some patients	[10,11,52,58,60,83]
Nevirapine	It is a non-nucleoside reverse transcriptase inhibitor. It inhibits the replication of the viral genome and helps in reducing viral load	Significant elevations in serum ALT levels leading to symptomatic impact on patient care	[10,11,13,52]
Umifenovir	It is a direct acting virucidal agent; it inhibits SARS-CoV-2 spike protein/ACE2 membrane fusion and hence inhibits viral entry into host cells	Elevated serum ALT levels	[10,11,52,59,60]
Antibiotics and antiparasitic agents
Ivermectin (anthelmintic drug)	Several mechanisms have been proven using in silico and in vitro studies like inhibition of viral entry, viral replication, and host importin α/β-1 of nuclear transport protein	Elevations in serum AST levels and clinically apparent liver damage	[10,11,13,52]
Chloroquine and hydroxychloroquine (antimalarial drug)	It has been proposed to inhibit the viral fusion with the ACE1 receptors and hence prevents viral entry into the host cells	Increased serum enzyme levels at high doses and trigger acute liver injury with sudden onset of fever	[10,11,13,52,60]
Azithromycin (macrolide antibiotic)	It inhibits viral entry into the host cells and also inhibits several cytokines	Elevated serum ALT levels and cholestatic hepatitis persisting even after discontinuing medication	[10,11,13,52]
Voriconazole	It is an antifungal agent and was used in the management of COVID-19-associated pulmonary aspergillosis	Elevated serum AST and ALT levels, and a case of acute liver failure had also been reported	[10,11,13,52]
Anidulafungin	It has been proposed that it acts by inhibiting viral protease and hence disrupts viral replication process in host cells	Transient elevation in serum ALT levels	[10,11,13,52]
Immunomodulatory agents
Tocilizumab (IL-6 receptor blocker)	It is an IL-6 receptor blocker and is approved for treatment of cytokine storm associated with COVID-19	Mild-to-moderate increase in serum ALT, AST levels and clinically apparent liver injury with jaundice, with the odds of at least one affected patient dying of liver injury	[10,11,13,52,60,84]
Dexamethasone (corticosteroid)	Reduces aggressiveness	Corticosteroids are associated with severe liver injury, which can cause hepatomegaly and steatosis and can trigger nonalcoholic steatohepatitis and sometime leads to liver failure and death	[10,11,13,52,60]
	Inflammatory response
Baricitinib	It is a Janus kinase inhibitor; it reduces inflammatory responses associated with COVID-19 infection	It is associated with idiosyncratic hepatotoxicity (possibly cholestatic) in patients with COVID-19. However, the liver damage has not been reported in COVID-19 patients so far	[67,68]
Tofacitinib
Imatinib
Colchicine	It has several potential anti-inflammatory mechanisms like inhibiting inflammasome signaling, reducing neutrophil chemotaxis, and reduced production of cytokines	Overdose of colchicine was associated with self-limiting liver injury	[10,11,13,52]
Miscellaneous therapies
Paracetamol	It has an antipyretic and analgesic effect and is widely used as an adjunct to reduce fever during COVID-19	Overdose of acetaminophen is associated with acute liver injury and when taken for several days at the therapeutic dose, there can be a slight increase in aminotransferases levels	[13,72,73]
Enoxaparin	It is low molecular weight heparin and was indicated in thromboembolic venous complications of COVID-19	Elevated serum AST levels and mild elevation in serum alkaline phosphate and total bilirubin levels	[10,11,13,52]
LMWH	It is an anticoagulant used in COVID-19 to reduce the risk of thromboembolism	LMWH are associated with acute hepatotoxicity, and elevations in the liver enzymes are usually observed after 5-8 d of initiation of therapy	[74,85]
SARS-CoV-2 vaccines (Pfizer-BioNTech, Moderna, and Oxford-AstraZeneca)	mRNA and viral vector encoding SARS-CoV-2 spike protein were used for vaccinations in healthy subjects	The clinical phenotype is mostly hepatocellular and showed features of immune-mediated hepatitis	[77,78]

ALT: Alanine aminotransferase; AST: Aspartate transaminase; ACE: Angiotensin converting enzyme; IL-6: Interleukin 6; LMWH: Low molecular weight heparin; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; COVID-19: Coronavirus disease 2019.