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A Systematic Review on Use of Liver Function Tests to Assess Association between Liver Injury and COVID 19 Disease

Richard Chinaza IKEAGWULONU, Nkereuwem Sunday ETUKUDOH, Mark Uchejeso OBETA*, Henry Chukwuemeka URO-CHUKWU, ImohEtim IBANGA

Department of Medical Laboratory Management, Federal School of Medical Laboratory Science, Jos, Nigeria

Abstract: BACKGROUND: As at 27th of June 2020, the COVID 19 pandemic had affected 9,653,048 people across the world including 491,128 deaths. We reviewed different studies on liver function tests in COVID 19 patients to better understand how the liver injury is associated with COVID 19 disease. METHODS: A review of the literature was carried out between18th May and 10thJune 2020 on the studies that investigated liver function tests in COVID 19 patients as a marker of liver injury in the patients. The databases used were Pubmed/Medline, Google Scholar and JSTOR and the search protocol involves a combination of words like laboratory diagnosis, liver function tests and COVID 19, SARS-COV-2 and coronavirus. RESULT: Twelve relevant articles were identified out of a total of 212 articles that were initially identified after duplicates were removed. The twelve articles reviewed comprise of 1,926 COVID 19 infected patients representing 1,003(52.1%) males and 923(47.9%) females. Comparing mild to severe cases of COVID 19, the most prevalent laboratory findings were increased AST (100%), ALT (91.7%) and total bilirubin (71.4%), as well as 100%, decreased serum level of albumin. CONCLUSION: Liver injury is associated with COVID 19 as evident with observed changes in serum levels of liver enzymes, bilirubin and albumin in these individuals.

Keywords: SARS-CoV-2, COVID-19, medical laboratory diagnosis, liver function tests

Received July 10, 2020; Revised July 24, 2020; Accepted August 02, 2020

Citation: Richard Chinaza IKEAGWULONU, Nkereuwem Sunday ETUKUDOH, Mark Uchejeso OBETA, Henry Chukwuemeka URO-CHUKWU, ImohEtim IBANGA, A Systematic Review on Use of Liver Function Tests to Assess Association between Liver Injury and COVID 19 Disease. International Journal of Celiac Disease, 8 (3). 110-116. January 2020. doi:10.12691/ijcd-8-3-8

1. Introduction

Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered coronavirus [1]. The novel coronavirus has not been previously identified in humans and it was first identified in Wuhan, Hubei Province of China in December 2019 (WHO 2020 2). Before the advent of COVID 19, other forms of coronaviruses like Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) exist and just like COVID 19 cause illness which ranged from the common cold to severe diseases [2]. The main target of COVID 19 is the respiratory system with an unexplainable case fatality rate such that as at 27 June, 2020, there were about 9,653,048 confirmed cases including 491,128 deaths worldwide [3]. COVID 19 cases in America, Europe and Africa as at June 27 2020 stood at 4816794, 2638903 and 268102 respectively [3] while in Nigeria confirmed cases were 23,298 with 554 deaths [4]. Severe pneumonia, acute cardiac injury, combined with the incidence of ground-glass opacities have been identified as the main pathogenesis of COVID 19 infection [5]. Unfortunately, up till now, there are no vaccines or targeted drugs used in the management of COVID 19, though in many countries, some drugs and vaccines are currently reported to be undergoing clinical trials.

COVID 19 infection has been associated with organ damage especially in its severe form [6,7]. Studies that highlighted the importance of substances like Vitamin D in preventing multiple organ damage induced by COVID 19 infection [8,9] also buttress to the fact that some level of organ damage does occur in infected patients. Laboratory studies have also shown an increase in pro-inflammatory markers [5,10] and hematological parameters [11] in COVID 19 infected patients. Varying degrees of liver Impairment occasioned by changes in liver function tests have equally been reported [7].

Furthermore, research is still evolving to fully understand how laboratory parameters can best be used to predict severity and prognosis of COVID 19 and in this study, the effort is made to systematically review and summarize findings from studies that investigated the association between liver injury and severity of COVID 19 infection.

2. Method

From May 18 to June 10, 2020, a literature search was conducted in Pubmed/Medline, Google Scholar and JSTOR for publications relating COVID 19 to changes in liver function tests. In this review liver function tests, also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver and includes tests like ALT, AST, ALP, GGT, Total bilirubin and albumin and globulin. The search protocol involves a combination of words like laboratory diagnosis, liver function tests and COVID 19, SARS-COV-2 and coronavirus. Reference lists of selected articles were also searched to identify missed studies. Time of publications was not restricted, however, only studies published in English were included. Studies were also included if they were primary research articles, assessed the association between serum levels of liver biochemical outcome from COVID 19 infection and reported in mean (SD) or median (IQR). Review articles, expert opinions, books, newsletters, commentaries, theses, editorials were all excluded. Patients were grouped as mild or severe cases. All patients in an intensive care unit (ICU) and non-survival cases were classified as severe cases whereas patients who are not in ICU and those that are survivors as seen in some studies were grouped as mild cases. All publications were retrieved online while data extraction was carried out for each paper highlighting the following: name of first author and year of publication, study design, study location, laboratory parameter, serum levels of the analytes, sample size, age, gender, and disease severity criteria. The search strategy and results are provided in Figure 1.

Figure 1. PRISMA Flow diagram for the selection of studies based on study inclusion and exclusion

3. Results

342 articles were found after the initial search of literature which was reduced to 212 articles following the removal of duplicates. Further evaluation of the titles, abstracts and full texts of the 212 articles applying the study inclusion and exclusion criteria aforementioned yielded a total of 12 articles which met the study criteria and were systematically reviewed in this study. All the reviewed studies (12-23) were retrospective in design and conducted in China except one done in Denmark. The twelve articles reviewed comprise of 1,926 COVID 19 infected patients representing 1,003(52.1%) males and 923(47.9%) females. The included articles characteristics are presented in Table 1. In all the studies, COVID 19 infection was identified using real-time reverse transcriptase-polymerase chain reaction (RT-PCR).

Table 1. General characteristics of reviewed articles

Table 2. Major findings from the reviewed studies

3.1. Alanine Aminotransferase

A total of twelve studies [12,13,14,15,16,17,18,19,20,21,22,23] investigated ALT levels in COVID 19 infected patients out of which 11 (91.7%) studies [12,14,15,16,17,18,19,20,21,22] reported increase in ALT. Of the eleven studies, the ALT increase in 3 (27.3%) studies were significant (P < 0.05) as against seven studies [12,14,15,17,18,20,21] were the increase was reported to be non-significant (P≥0.05). ALT level decreased in one study [13].

3.2. Aspartate Aminotransaminase

Ten studies [12,13,14,15,16,17,18,19,20,21] reported AST changes in COVID 19 infected patients and according to their findings, all the studies (100%) reported that AST levels were increased. The increase in AST was significant in eight studies [12,14,15,16,17,18,19,21] and non-significant in two studies [13,20].

3.3. Alkaline Phosphatase

ALP was investigated in two studies [14,16] and in the two studies, the serum level of ALP decreased in COVID 19 infected patients. The decrease was significant in one study [16] and non-significant in the other [14].

3.4. Gamma Glutaryl Transferase

Two studies [14,16] investigated GGT and reported an increase in serum GGT level in COVID 19 infected patients. The increase was significant in one study [16] and non-significant in the other [14].

3.5. Total Bilirubin

Total bilirubin was identified in seven studies [14,16,17,18,19,20,21]. Five of the seven studies [16,17,19,20,21] reported an increase in total bilirubin levels in COVID 19 infected patients. The increase was significant in three [16,17,21] of the five studies and non-significant in two studies [19,21]. An decrease in total bilirubin was reported in one study [14] whereas in another study [18] there is no change in serum level of total bilirubin.

3.6. Albumin

Albumin level was investigated in eight studies [12,13,14,17,18,19,20,23] and in all of them (100%), serum level of albumin significantly decreased in COVID 19 infected patients.

3.7. Globulin

A total of three studies [12,14,21] investigated globulin level in COVID 19 infected patients. According to two of the studies [12,14], serum level of globulin decreased non-significantly in the infected patient whereas a significant increase was seen in one study [21].

4. Discussion

The purpose of the present review was to figure out the laboratory characteristics of liver function tests of patients with COVID 19 and from this study, it is evident that COVID 19 is associated with liver damage. Any damage to the liver is associated with changes in liver enzymes and other substances that are either produced in the liver or are excreted through the liver. The level of these substances in the blood depends on the severity of the damage to the liver. The most prevalent laboratory findings in the present study were increased AST (100%), ALT (91.7%) and total bilirubin (71.4%), as well as 100%, decreased serum level of albumin. This result links severe cases of COVID 19 to liver damage. A similar systematic review and meta-analysis equally reported similar findings [24]. Also, a previous study that analyzed a cohort of patients who died of severe COVID 19 reported elevated levels of AST (79%), ALT (14%) and GGT (36%) in these patients [25]. Interestingly, studies have associated other forms of coronaviruses with liver damage [26,27]. The use of liver function tests (LFT) in the predicting severity of the liver injury is well documented in the work of [28] and AST is significant for stage 3 and 4 fibrosis [29]. The elevation of GGT shows the involvement of the biliary epithelial cells whereas the decreased in albumin is a pointer that the synthetic function of the liver is also impaired.

Medical laboratory science should not be neglected in the fight against COVID 19 [30,31,32], as the containment of the pandemic has a lot to do with such medical laboratory diagnosis and management of the severity among the patients.

5. Conclusion

Liver injury is associated with COVID 19 infection especially in its severe form and earlier detection and reversal of these effects can positively affect patient’s prognosis and survival.

Conflict of Interest

None.

Financial Assistance

None.

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