Acute liver injury in COVID-19 patients hospitalized in the intensive care unit: Narrative review

Table 1 Studies examining coronavirus disease 2019 induced acute liver injury in intensive care unit patients

Ref.	ALI definition	Number of ICU patients	ALI incidence	Major findings/outcomes
Roedl et al[28], 2021, Germany, Single-center, retrospective	↑ Transaminases > 20 × ULN or BIL ≥ 2 mg/dL	72	31%	ALI pts experienced higher mortality (83% for hepatocellular, 66% for mixed and 60% for cholestatic ALI), developed respiratory failure more frequently and had higher need for MV, ECMO, vasopressors and RRT
Huang et al[29], 2020, China, Single-center, retrospective	↑ALT > 20 × ULN	51	5.88%	ALI was not rare and was associated with high mortality due to MOF
Salik et al[30], 2021, Turkey, Single-center, retrospective	↑ALT/AST > 3 × ULN and/or ↑TBIL > 2 × ULN`	533	8.6%	ALI pts had higher total, 7-d and 28-d mortality, as well as higher SOFA score. ALI was more frequent in males
Arentz et al[31], 2020, United States, Single-center, case series	ALT or AST levels > 3 × ULN	21	14.3%	67% mortality for the overall cohort, no mortality data for ALI pts. All ALI pts (3) were on MV. High rate of cardiomyopathy in the overall cohort
Martinot et al[32], 2021, France, Single-center, retrospective observational cohort	AST ≥ 3 × ULN	153	9.8%	Factors associated with higher risk for ALI: Age > 75, cancer, cardiac disease, higher levels of CRP, serum Cr and Hb
Sun et al[33], 2020, China, Single-center, retrospective observational	↑Serum levels of liver biomarkers (e.g. ALT) > 2 × ULN or disproportionate ↑ALT/AST vs ALP	83	18.1%	The study focused on AGI, defined as various grades of malfunction of the GI tract, and not on ALI. Pts with worse AGI grades had higher 28-d mortality, higher incidence of septic shock and worse clinical variables
Cardoso et al[34], 2020, Portugal, Single-center, case series	Any elevation of at least one liver test (AST, ALT, ALP, GGT, TBIL) above ULN	20	100%	Liver injury was frequent, but transient and non-severe. Late cholestasis was mainly observed
Shousha et al[35], 2021, Egypt, Multi-center, prospective cohort	↑Transaminases > 3 × ULN	122 ICU pts. Overall cohort consisted of 547 pts	4.91% or 3.70% (based on AST or ALT levels respectively). Data represent overall (not ICU) pts cohort	FIB-4 on admission was significantly higher in pts admitted to the ICU, those with more severe COVID-19 and non-survivors. FIB-4 score > 3.25 and ICU admission were significant predictors of mortality
Currier et al[36], 2021, United States, Single-center, retrospective	ALT/AST > 60, ALP > 150, or BIL > 1.5	No data available for ICU pts. Overall cohort consisted of 8028 pts	45%. Data represent overall (not ICU) pts cohort	Black COVID-19 pts with liver test abnormalities were at greater risk for ICU admission and intubation compared to other races, but non-Black pts with liver test abnormalities were at increased risk of death
Rabiee et al[37], 2020, United States, Multi-center, observational cohort	ALT ≥ 2 × ULN (moderate: ALT 2-5 × ULN, severe: ALT > 5 × ULN)	30 ICU pts. Overall cohort consisted of 81 hospitalized LT recipients	34.6%. Data represent overall (not ICU) pts cohort	ALI was associated with higher risk for ICU admission and higher mortality. Hispanic ethnicity, metabolic syndrome, use of vasopressors, antibiotic use and younger age were independent risk factors for ALI. ICU pts were more likely to have their immunosuppression therapy modified
Roncati et al[38], 2022, Italy, Case report	N/A	2	100%	Fulminant herpetic hepatitis developed as a superimposed opportunistic infection due to tocilizumab-induced immunosuppression. Both pts died due to acute liver failure
Bütikofer et al[39], 2021, Switzerland, Single-center, retrospective cohort	Cholestatic ALI: ALP ≥ 1.5 × ULN and GGT ≥ 3 × ULN (termed severe if additionally TBIL ≥ 2 × ULN)	34	59% (27% severe)	Pts with severe ALI had higher mortality, significantly longer ICU stay with a more complicated course and required higher levels of support
Wendel-Garcia et al[40], 2022, Switzerland, Single-center, prospective observational cohort (post-hoc analysis)	Acute cholestatic liver injury: ALP > 1.5 × ULN and GGT > 3 × ULN (severe if additionally BIL > 2 × ULN)	243	47%	Pts who received ketamine had an increased risk of developing cholestatic liver injury than pts who didn’t. Ketamine infusion demonstrated a dose-dependency and duration-dependency association with increasing BIL and ALP levels, but it was not associated with increased hospital mortality

AGI: Acute gastrointestinal injury; ALI: Acute liver injury; ALT: Alanine transaminase; ALP: Alkaline phosphatase; AST: Aspartate transaminase; BIL: Bilirubin; COVID-19: Coronavirus disease 2019; Cr: Creatinine; CRP: C-reactive protein; ECMO: Extracorporeal membrane oxygenation; FIB-4: Fibrosis-4 index; GI: Gastrointestinal; GGT: Gamma-glutamyl transferase; Hb: Hemoglobin; ICU: Intensive care unit; LT: Liver transplant; MOF: Multiple organ failure; MV: Mechanical ventilation; Pts: Patients; RRT: Renal replacement therapy; SOFA: Sequential organ failure assessment; TBIL: Total bilirubin; ULN: Upper limit of normal.