key: cord-335355-lcrbs2op
authors: Kunutsor, Setor K.; Laukkanen, Jari A.
title: Markers of liver injury and clinical outcomes in COVID-19 patients: A systematic review and meta-analysis
date: 2020-05-28
journal: J Infect
DOI: 10.1016/j.jinf.2020.05.045
sha: 
doc_id: 335355
cord_uid: lcrbs2op

nan

Since January 2020 when it was first isolated in China, coronavirus disease 2019 (COVID-19) has spread throughout the world and caused substantial morbidity and mortality. ( abnormalities. In their analyses to explore prognostic factors for fatal outcomes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were not found to be independently associated with the risk of mortality. Though it has been reported liver injury is more prevalent in severe cases of COVID-19, (3, 4) whether circulating levels of markers of liver injury could predict clinical outcomes in COVID-19 patients is uncertain. In this context, we aimed to determine the nature of the relationships of admission levels of five main markers of liver injury (ALT, AST, gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP) and total bilirubin) with the risk of clinical outcomes in patients with COVID-19 using a systematic meta-analysis.

We conducted this review using PRISMA and MOOSE guidelines (Supplementary Materials 1-2) and in accordance with a registered protocol in the PROSPERO International prospective register of systematic reviews (CRD42020183672). MEDLINE, Embase, and The Cochrane library were searched from 2019 to 17 May 2020 for published studies reporting on relationships between admission levels of markers of liver injury (GGT, ALT, AST, ALP and total bilirubin) and clinical outcomes in patients with COVID-19. The detailed search strategy has been reported in Supplementary Material 3. Outcomes were categorised into severe illness and mortality.

Mean differences (95% CIs) for comparing mean levels of circulating markers across outcomes and relative risks (RRs) (95% confidence intervals, CIs) for associations between markers and outcomes were used as summary measures across studies. (5) The inverse variance-weighted method was used to effect estimates using random-effects models to minimize the effect of heterogeneity. STATA release MP 16 (StataCorp LP, College Station, TX, USA) was used for all statistical analyses.

Sixteen retrospective cohort studies comprising 10,540 COVID-19 patients were eligible ( Table 1 

In pooled results of two studies each, the RRs (95% CIs) of mortality associated with elevated ALT and AST were 3.35 (2.37-4.75) and 10.42 (7.05-15.40) respectively. In results from single studies, increased levels of ALP and total bilirubin were each associated with an increased risk of mortality (Supplementary Material 6). Admission levels of AST and total bilirubin were higher in those who died; whereas ALT levels were not significantly different in both groups: mean differences (95% CIs) of 17.13 U/L (11.25, 23.01; p<0.001); 4.21 µmol/l (3.97, 4.46; p<0.001) and 5.82 U/L (-2.57, 14.21; p=0.17) respectively. In single reports, levels of ALP and GGT were higher in those who died compared with survivors (Fig. 1B) .

Taking the overall evidence together, the data supports a higher prevalence of elevated admission levels of markers of liver injury in severe or mortality due to COVID-19 disease, which suggests that patients with elevated levels of liver markers at baseline (during admission) had higher risks of developing worse outcomes in COVID-19. The likely explanation for the worse outcomes observed in patients with baseline elevated markers of liver injury (as seen in chronic liver disease) could be attributed to compromised immune status. (3, 4) Irrespective of the fact that about 2-11% of patients with COVID-19 have liver comorbidities,(3) COVID-19 also causes liver injury. However, there is controversy regarding the causes of liver injury in COVID-19. (3, 4) Proposed explanations include (i) drug-induced liver injury;

(ii) direct injury to the liver due to COVID-19 hepatitis(4); (iii) COVID-19 induced myositis(4); (iv) binding of SARS CoV-2 directly to angiotensin-converting enzyme 2 (ACE2) positive rich cholangiocytes and causing liver damage;(6) (v) hepatic congestion due to high levels of positive end expiratory pressure during mechanical ventilation;(4) and (vi) aggravation of liver injury by SARS CoV-2 in patients with pre-existing viral hepatitis. (7, 8) In the absence robust association studies and formal risk prediction analyses, the overall evidence suggests that increased baseline levels of markers of liver injury could predict poor outcomes. The global prevalence of chronic liver disease remains high and continues to increase. Treatment options for COVID-19 are currently supportive; hence, there should be more intensive monitoring of levels of markers of liver injury during admission so that therapeutic approaches can be individually tailored.

There are several limitations which deserve mention. First, the heterogeneous reporting of severe illness outcomes prompted the use of composite measures. Second, the possibility of patient overlap as all 16 studies were reported from China; there have been concerns with duplicate reporting of study participants in articles.(9) Third, due to the limited sample sizes and low events, some studies were unable to assess risk ratios to quantify the relationships. Finally, though we extracted data on baseline (admission) levels of these markers, studies were not very specific regarding the exact time of blood sampling in relation to the disease status; hence, these results may have some biases.

In conclusion, elevated admission levels of markers of liver injury particularly the aminotransferases, may be associated with progression to severe disease or death in COVID-19.

Monitoring levels of these markers could assist in the optimum management of patients.

None. 

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Coronavirus disease 2019 in elderly patients: Characteristics and prognostic factors based on 4-week follow-up

Liver injury in COVID-19: management and challenges

COVID-19 and the liver: little cause for concern

Association of serum total osteocalcin with type 2 diabetes and intermediate metabolic phenotypes: systematic review and meta-analysis of observational evidence

Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection

Liver injury during highly pathogenic human coronavirus infections

Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement

Concern-Possible Reporting of the Same Patients With COVID-19 in Different Reports

Ruan, 2020Chen, 2020Subtotal

Yang, 2020Ruan, 2020