key: cord-0835730-c6nc8qjo
authors: Harapan, Harapan; Fajar, Jonny Karunia; Supriono, Supriono; Soegiarto, Gatot; Wulandari, Laksmi; Seratin, Fiha; Prayudi, Nyoman Gede; Dewi, Dara Puspita; Monica Elsina, Maria Theresia; Atamou, Lasarus; Wiranata, Sinta; Aprianto, Dhito Pemi; Friska, Erlin; Sari Firdaus, D. Fitria; Alaidin, Makdum; Wardhani, Firdha Aprillia; Husnah, Milda; Hidayati, Nurdina Wahyu; Hendriyanti, Yeni; Wardani, Kristia; Evatta, Arde; Manugan, Reizal Audi; Pradipto, Wiryawan; Rahmawati, Ade; Tamara, Fredo; Mahendra, Aditya Indra; Nainu, Firzan; Santoso, Budi; Irawan Primasatya, Chandra Adi; Tjionganata, Nindy; Budiman, Hendarto Arif
title: The prevalence, predictors and outcomes of acute liver injury among patients with COVID‐19: A systematic review and meta‐analysis
date: 2021-10-13
journal: Rev Med Virol
DOI: 10.1002/rmv.2304
sha: ece5ce27fe5b016b6ad7043f9983a217ef36f8e1
doc_id: 835730
cord_uid: c6nc8qjo

The data on the predictors and prognosis of acute liver injury (ALI) among patients in coronavirus disease 2019 (COVID‐19) patients are limited. The aim of this study was to determine the prevalence, predictors and outcomes of ALI among patients with COVID‐19. A systematic review was conducted up to 10 June 2021. The relevant papers were searched from PubMed, Embase, Cochrane and Web of Science, and the data were analysed using a Z test. A total of 1331 papers were identified and 16 papers consisting of 1254 COVID‐19 with ALI and 4999 COVID‐19 without ALI were analysed. The cumulative prevalence of ALI among patients with COVID‐19 was 22.8%. Male and having low lymphocyte levels were more likely to be associated with ALI compared with female and having higher lymphocyte level, odds ratio (OR): 2.70; 95% confidence interval (CI): 2.03, 3.60 and mean difference (MD) −125; 95% CI: −207, −43, respectively. COVID‐19 patients with ALI had higher risk of developing severe COVID‐19 compared with those without ALI (OR: 3.61; 95% CI: 2.60, 5.02). Our findings may serve as the additional evaluation for the management of ALI in COVID‐19 patients.

The data on the predictors and prognosis of acute liver injury (ALI) among patients in coronavirus disease 2019 (COVID- 19) patients are limited. The aim of this study was to determine the prevalence, predictors and outcomes of ALI among patients with COVID-19. A systematic review was conducted up to 10 June 2021. The relevant papers were searched from PubMed, Embase, Cochrane and Web of Science, and the data were analysed using a Z test. A total of 1331 papers were identified and 16 papers consisting of 1254 COVID-19 with ALI and 4999 COVID- 19 without ALI were analysed. The cumulative prevalence of ALI among patients with COVID-19 was 22.8%. Male and having low lymphocyte levels were more likely to be associated with ALI compared with female and having higher lymphocyte level, odds ratio (OR): 2.70; 95% confidence interval (CI): 2.03, 3.60 and mean difference (MD) −125; 95% CI: −207, −43, respectively. COVID-19 patients with ALI had higher risk of developing severe COVID-19 compared with those without ALI (OR:

3.61; 95% CI: 2.60, 5.02). Our findings may serve as the additional evaluation for the management of ALI in COVID-19 patients.

acute liver injury, COVID-19, outcome, predictor, prevalence

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains the major global concern. The pathogenesis of COVID-19 is complicated 1,2 and involves multiple organs including lung, kidney, heart, neurologic system, gastrointestinal system and liver. 3 Although the respiratory tract is the primary target of SARS-CoV-2, more than 50% of COVID-19 patients had nausea, vomiting, diarrhoea and loss of appetite 4 suggesting the involvement of gastrointestinal and hepatobiliary system. A recent study also found that moderate microvascular steatosis was prevalent in liver biopsies of COVID-19 patients, suggesting that liver injury might occur during COVID-19. 5 The involvement of liver in SARS-CoV-2 infection is mystifying, 6 and it was suggested that liver involvement is mediated by several mechanisms, including direct infection of the liver, drug-induced liver injury, systemic inflammatory response or hypoxic hepatitis. 7 The optimal management of acute liver injury (ALI) in COVID-19 patients remains controversial. Although one recommendation suggested that ALI in COVID-19 is reversible and does not require specific treatment, 7 liver involvement was reported to cause poor prognosis of COVID-19 patients. 8 Moreover, liver involvement has been included in predicting the outcomes of patients with COVID-19. 9 To date, no information is available regarding predictors of when and who among COVID-19 patients will suffer from ALI. In addition, data on the outcomes of COVID-19 patients with ALI are also limited. Therefore, the objective of this study was to determine the prevalence of ALI in COVID-19 patients, predictors of ALI occurrence and prognosis of COVID-19 patients with ALI. (2) report either the prevalence, predictor or the outcome of ALI in COVID-19 patients; (3) contain information about COVID-19 cases diagnosed using RT-PCR from nasopharyngeal or oropharyngeal swab samples; and (4) have sufficient criteria for the diagnosis of ALI. 11

All papers in English were searched using Medical Subjects Heading:

("COVID-19" OR "SARS-CoV-2") AND ("acute liver injury" OR "liver dysfunction" OR "liver abnormality") AND ("prevalence" OR "predictor" OR "outcome"). Additional papers from the reference list of the articles were searched and in case of dual duplication, a paper with the higher sample size was included. The following information were collected from each study: (1) first author name and publication

year; (2) country and city of origin; (3) study design; (4) study setting;

(5) sample size of COVID-19 patients with and without ALI; (5) the incidence of ALI; (6) the factors associated with ALI; and (7) severity and mortality rate of COVID-19 patients with and without ALI. The definition of variables and study protocols were defined prior to data collection, and a kappa test was used to assess the understanding among investigators.

Potential articles were evaluated for their methodological quality using Newcastle-Ottawa Scale (NOS) that evaluates sample selection, comparison and exposure. 12 The calculation of NOS score was used to classify the quality of articles into low (score 0-3), moderate (score 4-6) and high quality (score 7-9) and only articles with moderate and high quality were included into analysis. All letters to the editor, commentaries, case reports, case series and reviews were excluded.

ALI refers to an acute abnormality of liver blood tests and the development of a coagulopathy, but does not exhibit any alteration of consciousness in an individual without underlying chronic liver disease. 9 The predictor variables included age, gender, body mass index (BMI), the presence of comorbidities [diabetes mellitus (DM), coronary artery disease (CAD) and hypertension], pre-existing liver disease, as well as the levels of leucocytes, lymphocytes and neutrophils. Those variables were defined after considering the available data.

To assess the publication bias, an Egger test was applied and a p < 0.05 indicated potential publication bias. 13 The heterogeneity among studies was assessed using a Q test and the random effect model was used if the heterogeneity across the studies were observed (p < 0.10). 13 The prevalence of ALI, the associated predictors of ALI, and the association between ALI and the clinical outcomes of patients with COVID-19 were determined using a Z test. 

A total of 1331 papers were identified across the databases of which 1283 papers were excluded due to having irrelevant studies. Full-text assessment was conducted on 48 papers and additional 32 papers were excluded as they did not meet the eligibility criteria ( Figure 1 ).

16 papers consisting of two cross-sectional studies, three prospective studies and 11 retrospective studies were finally included into metaanalysis (Table 1) . 5,14-28

The (Figure 2d and Table 2 ).

The heterogeneity was identified on data of prevalence of ALI in COVID-19 patients, mortality of COVID-19 and data of some predictors of ALI such as age, hypertension, liver disease, WBC, neutrophils and lymphocytes and therefore random effect model was used while other predictors were and the association between ALI and severity of COVID-19 was assessed using fixed effect model. The potency of publication bias was found in several predictors of ALI including BMI, DM and CAD ( Table 2 ).

Our study found that the cumulative prevalence of ALI among patients with COVID-19 was 22.8%. This finding is higher compared with that of a previous meta-analysis using data of five studies (prevalence 15.7%). 29 Our data suggest that male and having high lymphocyte level were associated with ALI. Although the mechanism of ALI in SARS-CoV-2 infection is debatable, it is known that the expression of angiotensin-converting enzyme 2 (ACE2) receptors, the primary receptor for SARS-CoV-2 to enter human cells, was high in the liver. 30 A previous investigation reported that the expression of ACE2 receptors was higher in male than female 31 and ACE2 expression is mediated by androgen. 32 A study revealed that ACE2 receptors were also expressed in lymphocytes, 33 suggesting that SARS-CoV-2 may also attack lymphocytes leading to decreased numbers. Interestingly, our study also found that patients with higher BMI and DM had higher risk to develop ALI, although the Egger test is insufficient to support the findings. The liver abnormality in patients with the obesity and DM suggested that the metabolic associated steatohepatitis might also affect the involvement of liver injury, and this circumstance might also contribute to the severity of COVID-19 infection. 31 Our findings also showed that COVID-19 patients with ALI had higher risk of developing severe disease, consistent with previous meta-analyses. 29 

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