Liver dysfunction and SARS-CoV-2 infection

Table 1 Principal studies about liver damage in coronavirus disease 2019 patients

Ref.	Study	Findings
Mao et al[15]	SR (35 studies, n = 6686)	The prevalence of abnormal liver functions was 19% (CI: 9-32). Patients with severe COVID-19 had higher rates of abnormal liver function including increased ALT (OR: 1.89, CI: 1·30-2·76) and increased AST (OR: 3.08, CI: 2.14-4.42) compared with those with non-severe disease
Wijarnpreecha et al[16]	SR (64 studies, n = 11245)	The prevalence of elevated AST, ALT, total bilirubin, GGT, and alkaline phosphatase was 23.2%, 21.2%, 9.7%, 15.0%, and 4.0%, respectively. The prevalence of elevated AST was higher among those with severe cases (45.5%) compared to non-severe cases (15.0%). Co-existing CLD presented in up to 37.6% of patients with COVID-19
Wang et al[17]	Single-center retrospective study (n = 105)	Fifty-six percent of the patients had abnormal ALT, AST, or total bilirubin during the illness (91.4% cases were ≤ 3 fold of the ULN). The percentage of patients with elevated both ALT and AST was 12.7% in mild cases vs 46.2% in severe cases. One third of patients with severe disease started to have abnormal ALT after admission, and 73.3% of all patients had normal ALT before discharge
Lei et al[18]	Multicenter retrospective cohort study (n = 5771)	The distributional and temporal patterns of liver injury indicators were following: AST elevated first, followed by ALT, in severe patients. Alkaline phosphatase modestly increased during hospitalization and largely remained in the normal range. The fluctuation in total bilirubin levels was mild in the non-severe and severe groups
Xie et al[19]	Retrospective study (n = 79)	Logistic regression analyses suggested that the extent of pulmonary lesions on CT was a predictor of liver function damage
Wu et al[20]	SR (45 studies, n = 7228)	The incidence of any abnormal liver biochemical indicator at admission and during hospitalization was 27.2% and 36%, respectively
Kulkarni et al[21]	SR (107 studies, n = 20874)	The prevalence of CLD was 3.6% (CI: 2.5-5.1). The incidence of elevated liver chemistries was 23.1% (CI: 19.3-27.3) at initial presentation and 24.4% (CI: 13.5-40) during the illness. The incidence of DILI was 25.4% (CI: 14.2-41.4). The prevalence of CLD among 1587 severely infected patients was 3.9% (3%-5.2%). CLD was not associated with the developing severe COVID-19 (OR: 0.81, CI: 0.31-2.09) compared to non-CLD patients. COVID-19 patients with elevated liver chemistries had an increased risk of mortality (OR: 3.46 CI: 2.42-4.95) and severe disease (OR: 2.87, CI: 2.29-3.6) compared to patients without
Mendizabal et al[22]	Multicenter prospective cohort study (n = 1611)	Abnormal liver tests on admission were present on 45.2% and were independently associated with death (OR: 1.5, CI: 1.1-2.0), and severe COVID-19 (OR: 2.6, CI: 2.0-3.3). The prevalence of CLD was 8.5%
Wong et al[23]	SR (24 studies, n = 5961)	In subjects with critical COVID-19, the OR of hypoalbuminemia was 7.1 (CI: 2.1-24.1), of AST elevation was 3.4 (CI: 2.3-5.0), of ALT elevation was 2.5 (CI: 1.6-3.7), and of hyperbilirubinemia was 1.7 (CI: 1.2-2.5)
Zhu et al[24]	SR (34 studies, n = 6492)	Patients with severe COVID-19 showed significantly longer PT, and a longer PT was associated with a higher risk to die
Elshazli et al[25]	SR (52 studies, n = 6320)	Prolonged PT was associated with a higher risk of progression to severe COVID-19 (OR: 1.82) and ICU admission (OR: 2.18)
Wu and Yang[26]	SR (13 studies, n = 3722)	The comparison between survivors and non-survivors with severe COVID-19 patients showed an OR of 1.98 (CI: 1.39-2.82) for liver dysfunction and mortality
Richardson et al[29]	Multicenter prospective cohort study (n = 5700)	In hospitalized COVID-19 patients, AST and ALT were both commonly increased (58.4% and 39.0% of patients, respectively). Fifty-six (2.1%) subjects developed a severe acute liver injury with a mortality of 95%
Shi et al[30]	Two-center retrospective study (n = 81)	Abnormal liver function test was found in patients with subclinical disease (elevated AST in 8.7% and elevated ALT in 8.9%
Sultan et al[58]	SR (47 studies, n = 10980)	The prevalence estimates of elevated liver abnormalities were as follows: AST 15.0% (CI: 13.6-16.5), ALT 15.0% (CI: 13.6-16.4), and abnormal bilirubin 16.7% (CI: 15.0-18.5)

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CI: Confidence interval; CLD: Chronic liver disease; COVID-19: Coronavirus disease 2019; CT: Computed tomography; DILI: Drug-induced liver injury; GGT: Gamma-glutamyltransferase; ICU: Intensive care unit; PT: Prothrombin time; OR: Odds ratio; SR: Systematic review; ULN: Upper limit of normal.

Table 2 Therapeutic management of patients with coronavirus disease 2019 and hepatotoxicity

Medication	Hepatotoxicity	Action mechanism	Currently recommended use for COVID-19
Hydroxychloroquine	Likelihood score: D (possible). Rare cause of clinically-apparent liver injury	Altered metabolism of other medications	Not recommended
Azithromycin	Likelihood score: A (well-known). Transient and asymptomatic elevation in serum aminotransferases; Typical cholestatic hepatitis	Unknown	Not recommended
Ivermectin	Likelihood score: D (possible). Mild elevation of serum aminotransferases; Reports of acute liver failure	Unknown	Not recommended
Dexamethasone	Likelihood score: A (well-known). Long-term use effects; Symptoms usually represent the worsening or triggering of an underlying liver disease	Drug-associated fatty liver disease	Recommended as emergency use
Remdesivir	Likelihood score: D (possible). Mild to moderate transient elevation of serum aminotransferases	Inhibition of mitochondrial RNA polymerase or idiosyncratic injury	Recommended as emergency use
Lopinavir/ritonavir	Likelihood score: D (possible). Moderate to severe elevation of serum aminotransferases (pattern hepatocellular to cholestatic or mixed); Duration 1-2 mo; Reports of acute liver failure; Caution in patients with co-infection by hepatitis B virus-hepatitis C virus-human immunodeficiency virus	Inhibits both of the isoforms of CYP3A del P450, which may result in production of a toxic intermediate	Not recommended
Baricitinib	Likelihood score: E (unlikely). Moderate transient elevation of serum aminotransferases (17% of patients); Hepatitis B reactivation	Unknown	Recommended as emergency use
Tocilizumab	Likelihood score: C (probably). Mild to moderate transient elevation of serum aminotransferases; Duration 8 wk	Unknown	Recommended as emergency use

COVID-19: Coronavirus disease 2019.