To determine the Effect of deranged Liver Enzymes on the Clinical Course and Outcome of

COVID-19 at Jinnah Hospital, Lahore, Pakistan.

Abstract

Introduction: The COVID-19 first case documented in Pakistan in February, 2020. Deranged

liver enzymes are one of the extra-pulmonary clinical manifestations of COVID-19 disease.

Objective: To determine the alterations in liver function tests (LFTs) in COVID-19 subjects

admitted at HDU of Jinnah hospital, Lahore, and its association with severity and prognosis of

disease.

Materials & Methods: This prospective cross-sectional research was conducted at HDU of

Jinnah hospital, Lahore. COVID-19 confirmed 100 patients (Male 54, Female 46) diagnosed via

PCR, were selected and included in the study and all patients were advised LFTs at the time of

first presentation and descriptive statistics were applied to find its association with COVID-19.

Results: COVID-19 subjects having increased age and having comorbidities were at risk of

developing severe COVID-19 disease and prognosis was also found to be disturbed more in such

patients. LFTs were found to be more likely to be deranged in severe category patients, with

Aspartate Aminotransferase, Alanine Aminotransferase and bilirubin levels significantly

associated with severity and outcome of COVID-19.

Conclusion: Deranged liver enzyme levels were found to be highly correlated with COVID-19

outcome and clinical course.

Keywords: LFTs; AST; ALT; COVID-19.

1
INTRODUCTION

COVID-19 disease began as an outbreak in late 2019 in China and started spreading to other

parts of world as a pandemic in early 2020. 1 It begun as an outbreak in Pakistan in February,

2020 and was declared as a global threat by WHO in March 2020.2,3 According to world-meter of

coronavirus, by mid August 2020, this virus caused 289,215 cases and 6,175 deaths in Pakistan. 2

There is a significant mortality rate, disease burden, and adverse economic and health sector

adverse effects of this virus.4,5

This acute respiratory syndrome is caused by corona virus 2 (SARS-CoV-2). 6 There are several

pulmonary and extra-pulmonary manifestations of this virus. 6 These manifestations can be linked

to higher affinity of Angiotensin-converting enzyme 2 (ACE-2) for SARS-CoV-2. 7 The ACE-2

is present in multiple organ systems such as heart, liver, kidney, and lungs. 7 This SARS-CoV-2

get binds to ACE-2 with 10-12 times higher affinity via receptor binding spike glycoprotein,

which results in severe pneumonia or severe acute respiratory syndrome, and other extra-

pulmonary manifestations.8

Deranged liver function tests can be one of the prominent extra-pulmonary manifestations of this

disease.9 The COVID-19 patients admitted in ICU were found to be more likely to have their

LFTs deranged that may be due to the severity of COVID-19 disease. 9 The derangement of LFTs

is also found to be due to the binding of SARS-CoV-2 to ACE-2 receptors present at ductal

system of liver which causes microvascular steatosis, micro-thrombosis, lobular necrosis and

blockage of lobular and portal activity.7,8,10,11

Review of the literature showed that deranged LFTs were found to be in at least one half or 15-

45% of COID-19 patients admitted in ICU or HDU.11-13 Therefore following this rationale, the

present study was conducted to determine the alterations in liver function tests (LFTs) in

2
COVID-19 patients admitted at HDU of Jinnah hospital, Lahore, and its association with severity

and prognosis of disease.

3
MATERIALS & METHODS

This Comparative Cross-Sectional Study was conducted after taking informed consent and ethics

approval at COVD HDU, Jinnah Hospital/AIMC, Lahore, over 45 days (from 20 June 2020 to 3

August 2020). The sample size was not calculated due to limited data available. A sample of 100

COVID-19 patients was included using non probability consecutive sampling technique.

Inclusion Criteria:

• COVID-19 confirmed patients as per WHO interim guidance & meeting the following

criteria: Epidemiology history, (b) Fever or other pulmonary symptoms, (c) Typical chest

X-ray appearance, and (d) RT-PCR + for SARS-CoV-2.3

• Willing to participate in study

Exclusion Criteria:

 Pre-existing hepatic issues.

 Liver function tests not performed on first presentation.

DATA COLLECTION PROCEDURE

A total of 100 COVID-19 confirmed patients were included in this study as per selection criteria.

All patients were advised LFTs at the time of first presentation. The following LFTs were

advised:- serum Alanine Aminotransferases (ALT), Aspartate Aminotransferases (AST) and

Total Bilirubin. Patients were divided in to mild, moderate, severe and critical categories on the

basis of severity as issued by NHSRC, government of Pakistan. The mild and moderate COVID-

19 patients taken as non-severe patients while severe and critical patients were considered as

severe patients.

4
Data was collected using pre-tested pre-designed proforma and following details were collected

and recorded: demographic data, age, gender, contact history & medical history, and LFTs i.e.

serum Alanine Aminotransferases (ALT), Aspartate Aminotransferases (AST) and Total

Bilirubin.

DATA ANALYSIS

Quantitative data were presented by mean ± SD & will be compared using ANOVA test.

Qualitative data were presented by frequency and percentages & will be compared using Fisher

exact test. Logistic Regression was applied on significant association of continuous variables

with severity.

5
RESULTS

100 COVID-19 patients (Male 54 (54%), Female 46 (46%)) with mean age of 53.61 ± 16.04

years, were included in the study.

On the basis of severity classification, 15 % (N = 15) patients were mild (mean age 46.59 ±

15.04 years), 27 % (N = 27) were moderate (mean age 47.12 ± 16.01 years), 39 % (N = 39)

patients were severe (mean age 54.54 ± 14.11 years), and 19 % (N = 19) patients were critical

(mean age 56.22 ± 17.07 years). The age (p = 0.004), and co-morbidities (p = 0.001) differences

were significant between severe and non-severe patients in determining disease severity, but

insignificant gender differences (p = 0.541) and contact history differences (p = 0.433) were

found between the two groups.

The ALT (p = 0.002), and AST (p = 0.001) values for Severe/Critical patients were significantly

higher while bilirubin (p = 0.567) values statistically insignificant as compared to the non-severe

patients (Figure 1) (Table 2).

Logistic Regression analysis showed that increase in Age (p = 0.004) and increase in ALT (p =

0.002), and AST (p = 0.001) levels were significantly associated with severity of disease (Table

3).

6
Table 1: Data of included patients

Variable Presented by Values

Age Mean ± S.D. 53.61 ± 16.04 Years

Gender Frequency / % 54 (54%) Male

46 (46%) Female

No Co-morbidities (NC) Frequency / % 12 (12%) NC

Diabetic and/or Hypertensive 88 (88%) DM/HT

(DM/HT)

Positive contact history Frequency / % 37 (37%)

Mild Patients Frequency / % 15 (15%)

Moderate Patients Frequency / % 27 (27%)

Severe Patients Frequency / % 39 (39%)

Critical Patients Frequency / % 19 (19%)

7
 Table 2: Comparison

Variable Severe % (N) Non-Severe % (N) Total % (N) p

Age 56.22 ± 17.07 46.59 ± 15.04 53.61 ± 16.04 0.004

Male 21 33 54(54) 0.541

Female 21 25 46 (46) 0.541

Positive Contact History 18 19 36 (36) 0.433

Co-morbidities (DM/HT) 51 37 88 (88) 0.001

ALT 61.22 (± 34.13) 43.76 (± 25.67) 48.12 (±27.12) 0.002

(IU/L)
AST 68.11 (± 25.12) 41.33 (± 17.60) 45.12 (±19.32) 0.001

(IU/L)
Bilirubin (mg/dl) 1.4678 (± 0.91) 1.4111 (±0.31) 1.3566 (±0.34) 0.567

8
Table 3: Logistic Regression Analysis

Variable Odds Ratio Confidence Interval (95%) p

Lower value Upper value

Age 1.021 1.010 1.149 0.003

ALT (IU/L) 1.01 1.002 1.222 0.002

AST (IU/L) 1.08 1.001 1.132 0.001

Total Bilirubin (mg/dl) 5.753 0.231 65.567 0.567

9
 80

70

60

50

40
Severe
30 Non-severe

20

10

0
Mean ALT (UI/L) Mean AST (UI/L) Mean Bilirubin
(mg/dl)

Figure 1: Comparison of LFTs levels.

10
DISCUSSION

The local data is limited regarding alterations in liver function tests in COVID-19 patients

admitted at HDU of Pakistani hospitals. Therefore, the aim was to determine the alterations in

LFTs in COVID-19 subjects admitted at HDU of Jinnah hospital, Lahore, and its association

with severity and prognosis of disease.

The results showed that COVID-19 was more common in male as compared to female; this is in

agreement with the findings of recently conducted study in China and Pakistan, where it was also

found that COVID-19 was more common in male as compared to female. 14,15 The mean age was

53.61 ± 16.04 years, this is also in agreement with the findings of recently conducted study in

China and Pakistan,14-17 where it was also found that COVID-19 patients’ mean age was around

50 years, however, this is in contrast with the findings of recently conducted study in France,

where it was also found that COVID-19 patients’ mean age was around 45 years.18

Patients were divided in to mild, moderate, severe and critical categories on the basis of severity

as issued by NHSRC, government of Pakistan. The results showed that 41 % patients were non-

severe, while 58% were severe patients. This is in contrast with the findings of recently

conducted two studies in China, where majority of the patients were non-severe.15,19

The age and co-morbidities differences were significant between severe and non-severe patients

in determining disease severity, but insignificant gender differences and contact history

differences were found between the two groups. This is in agreement with the findings of

recently conducted study in China and Pakistan,14-17 where it was found that increasing age and

co-morbidities are linked with severity of disease but not the gender or contact history.

11
The ALT, and AST values for Severe/Critical patients were significantly higher and logistic

regression analysis also showed that increase in ALT, and AST levels for Severe/Critical

patients. This is in agreement with the findings of recently conducted two studies in China. 15,20

However, this is in contrast with the findings of another recently conducted study in China,21

where it was also found that ALT, AST, and bilirubin levels were not significantly associated

with severity of COVID-19 disease. The results of the present study showed that LFTs can be

used as markers to monitor status of COVID-19 admitted patients and to prepare for advanced

intensive life saving care, if required.

There are several limitations of this study such as small sample size, single centre study and lack

of long follow-ups. However, within these limitations the result of the present study showed that

deranged liver enzyme levels were found to be highly correlated with COVID-19 disease

severity and prognosis. Further large scale studies with longer follow-up periods are suggested to

determine the alterations in liver function tests in COVID-19 admitted patients, and its

association with COVID-19 outcome and clinical course.

12
CONCLUSION

Deranged liver enzyme levels were found to be highly correlated with COVID-19 disease

severity and prognosis.

13
REFERENCES

1. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease

(COVID-19) outbreak. J Autoimm. 2020 Feb 26:102433.

2. Waris A, Khan AU, Ali M, Ali A, Baset A. COVID-19 outbreak: current scenario of

Pakistan. New Microb New Infect. 2020 Apr 14:100681.

3. World Health Organization. Mental health and psychosocial considerations during the

COVID-19 outbreak, 18 March 2020. World Health Organization; 2020.

4. Ji Y, Ma Z, Peppelenbosch MP, Pan Q. Potential association between COVID-19

mortality and health-care resource availability. Lancet Global Health. 2020 Apr

1;8(4):e480.

5. Miller IF, Becker AD, Grenfell BT, Metcalf CJ. Disease and healthcare burden of

COVID-19 in the United States. Nature Medicine. 2020 Aug;26(8):1212-7.

6. Cheng H, Wang Y, Wang GQ. Organ‐protective effect of angiotensin‐converting enzyme

2 and its effect on the prognosis of COVID‐19. J Medical Virology. 2020 Mar 27.

7. Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor

blockers may increase the risk of severe COVID-19. J Travel Med. 2020 Mar 18.

8. Tolouian R, Vahed SZ, Ghiyasvand S, Tolouian A, Ardalan M. COVID-19 interactions

with angiotensin-converting enzyme 2 (ACE2) and the kinin system; looking at a

potential treatment. J Renal Injury Prev. 2020 Mar 30;9(2):e19-.

9. Bangash MN, Patel J, Parekh D. COVID-19 and the liver: little cause for concern. The

Lancet. Gastroent Hepatol. 2020 Jun;5(6):529.

14
10. Zhang Y, Zheng L, Liu L, Zhao M, Xiao J, Zhao Q. Liver impairment in COVID‐19

patients: A retrospective analysis of 115 cases from a single centre in Wuhan city, China.

Liver International. 2020 Apr 2.

11. Li J, Fan JG. Characteristics and mechanism of liver injury in 2019 coronavirus disease. J

Clinical Translational Hepatology 8 (2020): 13.

12. Fan Z, Chen L, Li J, et al. Clinical features of COVID-19-related liver damage. Clinical

Gastroent Hepatol. (2020).

13. Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges.

Lancet Gastroent Hepatol 5 (2020): 428-430

14. Ahmed M, Umar M, Sufyan A, Zeb S, Ahmad H, Shahid R. Liver Function Tests; a

Marker of Severity in Covid 19 Patients. Austin Hepatol. 2020;5(1):1013.

15. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected

with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395: 497-506.

16. Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, et al. Radiological findings from 81

patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet

Infectious Diseases. 2020.

17. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of chest CT and RT-PCR

testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases.

Radiology. 2020; 200642.

18. Gautret P, Lagier JC, Parola P, Meddeb L, Mailhe M, Doudier B, et al.

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-

label non-randomized clinical trial. International J Antimicrob Agents. 2020; 105949.

15
19. Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, et al. Comorbidity and its

impact on 1590 patients with Covid-19 in China: A Nationwide Analysis. European

Respir J. 2020.

20. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of 2019

novel coronavirus infection in China. MedRxiv. 2020.

21. Yang X, Yu Y, Xu J, Shu H, Liu H, Wu Y, et al. Clinical course and outcomes of

critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered,

retrospective, observational study. Lancet Respiratory Medicine. 2020.

16