key: cord-0747669-38hgg0jz
authors: Kumar, Abhishek; Kumar, Piyush; Dungdung, Ajit; Kumar Gupta, Anitesh; Anurag, Aditya; Kumar, Abhinav
title: Pattern of liver function and clinical profile in COVID-19: A cross-sectional study of 91 patients
date: 2020-10-06
journal: Diabetes Metab Syndr
DOI: 10.1016/j.dsx.2020.10.001
sha: 549cd26ee5a946b6bec5b3a90af470104cb20dea
doc_id: 747669
cord_uid: 38hgg0jz

BACKGROUND: – COVID-19 caused by SARS-CoV-2 leads to myriad range of organ involvement including liver dysfunction. AIM: To analyse the liver function in patients with COVID-19 and their association with respect to age, sex, severity of disease and clinical features. MATERIALS AND METHODS: This study was a cross-sectional study done at Rajendra Institute of Medical Sciences, Ranchi. 91 patients admitted with confirmed SARS-CoV-2 infection were included in this study and divided into asymptomatic, mild, moderate and severe groups. Liver function tests were compared among different severity groups. RESULTS: Of 91 patients with COVID-19, 70 (76.9%) had abnormal liver function. Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin levels was 1–2 × ULN in 33(36.3%), 34(37.3%), 12(13.2%), 6(6.6%) cases and >2 × ULN in 20(22%), 18(19.8%), 7(7.7%) and 2 (2.2%) cases respectively. Mean AST and ALP levels among different severity groups of COVID-19 was statistically significant (p < 0.05) whereas mean ALT and total bilirubin levels was statistically non-significant (p > 0.05). There was no statistical difference between males and females with regard to abnormal liver function. Liver injury was seen in 64.3% cases of hypertension and 73.3% cases of diabetes. Fever, myalgia, headache and breathlessness were found to be correlated significantly with severity of disease. CONCLUSION: Liver injury is common in SARS-CoV-2 infection and is more prevalent in the severe disease group. Aspartate transaminase and alkaline phosphatase are better indicators of covid-19 induced liver injury than alanine transaminase and total bilirubin.

RESULTS-Of 91 patients with COVID-19, 70(76.9%) had abnormal liver function. Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin levels was 1-2 × ULN in 33(36.3%), 34(37.3%), 12(13.2%), 6(6.6%) cases and > 2 × ULN in 20(22%), 18(19.8%), 7(7.7%) and 2(2.2%) cases respectively. Mean AST and ALP levels among different severity groups of COVID-19 was statistically significant (p<0.05) whereas mean ALT and total bilirubin levels was statistically nonsignificant (p>0.05). There was no statistical difference between males and females with regard to abnormal liver function. Liver injury was seen in 64.3% cases of hypertension and 73.3% cases of diabetes. Fever, myalgia, headache and breathlessness were found to be correlated significantly with severity of disease.

CONCLUSION-Liver injury is common in SARS-CoV-2 infection and is more prevalent in the severe disease group. Aspartate transaminase and alkaline phosphatase are better indicators of covid-19 induced liver injury than alanine transaminase and total bilirubin.

3. KEYWORDS: COVID-19, SARS-CoV-2, liver dysfunction, clinical profile

On 31st December 2019, China reported cases of pneumonia of unknown etiology related to Hunan sea food market in Wuhan. [1] . A new strain of Coronavirus was later identified as the causative agent. The virus was renamed by WHO as SARS-CoV-2 and the disease as COVID-19. [2] Since its detection, the disease has spread to 270 countries with 24,555,405 cases and 802,762 deaths reported worldwide. India has reported 3,621,245 cases and 64,469 deaths until the time of writing this report. [3] The transmission of SARS-CoV-2 can occur via respiratory secretions directly through droplets from coughing, sneezing or indirectly through contaminated objects or surfaces as well as close contacts. [4] COVID-19 poses a huge risk for the already overloaded and inadequate health infrastructure of India.

The main manifestations of COVID-19 include fever, cough, breathlessness, myalgia, malaise, headache, nausea, vomiting, diarrhea. [5] Cases of seizures, thrombosis-induced-myocardial infarction, neuropathy have also been reported. [6] [7] [8] Liver function abnormality has been reported in patients with COVID-19. [9] Based on clinical severity, COVID-19 has been divided into mild, moderate and severe disease. Mild disease: uncomplicated upper respiratory tract infection with mild symptoms such as fever, cough, sore throat, nasal congestion, malaise, headache with normal SpO2 levels; Moderate disease: pneumonia and no signs of severe disease, SpO2 90-94% on room air, respiratory rate 24-30/min; Severe disease: severe pneumonia with signs of respiratory distress, respiratory rate >30/min or SpO2 <90% on room air. [10] Studies with the help of single-cell RNA sequencing technique have confirmed ACE-2 receptors to be the entry receptor of SARS-CoV-2. [11] ACE-2 receptors are present in the bile duct cells 20 times more than that in hepatocytes.

SARS-CoV-2 may infect the hepatocytes and bile duct cells and cause liver dysfunction. [12] Studies have shown the presence of pathological changes like moderate micro-vescicular steatosis, lobular and portal activity in a series of liver biopsies, indicating that liver injury may be either due to SARS-CoV-2 induced direct hepatocellular injury or drug induced. [13] Findings from a series of autopsies conducted at Mount J o u r n a l P r e -p r o o f 4 Senai, New York reported blood clots in the brain, kidney and liver reflecting endothelial damage, activation of the coagulation cascade and persistently raised elevation of inflammatory markers suggesting the possible additional role of systemic thrombo-embolism in liver function abnormality among COVID patients. [14] In view of the pathogenicity, infectivity and the high incidence of liver damage, an in-depth study of liver dysfunction in these patients is the need of the hour. In this study, we aimed to analyse the liver function abnormalities in patients with COVID-19 and their association with respect to age, sex, severity of disease and clinical features.

Our study was a single centre, cross-sectional study in Rajendra Institute of Medical Sciences, Ranchi, Jharkhand (dedicated COVID hospital of the region). 91 patients with confirmed real-time polymerase chain reaction status for SARS-CoV-2 admitted and treated from 1 st to 15 th August, 2020 were included in this study. The study was approved by the Institutional ethics committee, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India. Informed consent was taken from every patient included in the study. Patients 

Patients with confirmed Real-Time Polymerase Chain Reaction for SARS-CoV-2 were included in this study.

Patients with pre-existing liver disease, alcoholics, Hepatitis B, Hepatitis C, those on drugs known to be hepatotoxic were excluded from the study. ALT, ALP and total bilirubin were grouped into normal (< ULN), 1-2 ULN and >2 ULN and their frequencies in various severity groups were studied. Abnormal liver function test was defined as elevation of any of the liver enzymes and/or total bilirubin more than upper limit of normal value.

Categorical data were expressed as percentages and groups were compared using the chi-square (X2) test.

Student's t test was applied to compare continuous data of two groups. One-way analysis of variance (ANOVA) was used to compare continuous data of more than two groups. The level of statistical significance was p <0.05. All hypothesis tests were 2-tailed. SPSS software version 21.0 was used to perform the analysis.

The clinical characteristics and liver function tests of the subjects on admission was tabulated ( respectively (p= 0.186). The male-female ratio in the entire study was 2:1. Male-female ratio among group I was 1:1 vs 2.5:1 in group II vs 3:1 in group III vs 1.3:1 in group IV (p = 0.508). The proportion of males and females with abnormal liver function was 77% and 76.6% respectively (p= 1.00).

The statistical analysis of liver function tests has been presented in Table 1 . On analysis of ALT levels, 52 of 91 (57.1%) subjects had elevated ALT levels, out of which 18 had levels > 2 ULN (34.6%) and 34 had levels between 1-2 ULN (65.4%) and 39 had normal ALT levels (42.9%). Significant difference in the distribution of ALT at different levels among groups I, II, III and IV was noted (p= 0.004) ( Table-1 On analysis of ALP levels, 19 of 91 (20.8%) subjects had elevated ALP levels, out of which 7 had levels > 2 ULN (36.8%) and 12 had levels between 1-2 ULN (63.2%) and 72 had normal ALP levels (79.2%).

Significant difference in distribution of ALP at different levels among groups I, II, III and IV was noted (p < 0.001) ( Table-1 (Table-2 ). The highest level of ALP was 434 U/L, in a subject of group III.

On analysis of total bilirubin levels, 8 of 91 (8.8%) subjects had elevated total bilirubin levels. No significant difference was observed in distribution of total bilirubin at different levels among groups I, II, III and IV (p= 0.301) ( Table-1 ). Mean total bilirubin in group I was 1 ± 0.0 mg/dL, in group II was 1.04 ± 0.19 mg/dL, in group III 1.08 ± 0.28 mg/dL, in group IV 1.26 ± 0.60 mg/dL (p= 0.082). Mean values of total bilirubin (mg/dL) among different groups was statistically non-significant (Table-2 ). The highest level of total bilirubin was 6 mg/dL, in a subject of group IV. In our study, mortality rate was 2(2.1%). Both patients had severe COVID-19 disease with ARDS.

Diabetes and hypertension were present in 16 

The median age in our study was 44 years (IQR: 29, 58; Range: 15-82) and 61 of 91 patients were male (67%). This is consistent with a previous report. [15] A recent Indian study reported median age of 33 years. [16] SARS-CoV-2 infection was more common in males (67%) than females (23%) as consistent with other studies. [17] [18] [19] [20] Patients with liver dysfunction in our study were more likely to be males (67.1%) than females (22.9%). However, among each sex group, liver dysfunction was similar i.e. 77% in males and 76.6% in females which is different from other studies showing males with more prevalence of liver dysfunction [16, 21] .

Abnormal LFTs were observed in 73.6% patients which is similar to other studies. [16, 18, 20] AST and ALT was elevated in 58.2% and 57.1% cases respectively which is similar to previous studies. [16, 21, 22] In our study, the levels of AST and ALP between different groups of disease severity was highly significant which is consistent with a previous report. [15] However, mean values of ALT and total bilirubin between different groups was statistically non-significant. This suggests AST and ALP values are indicative of severity of the disease and increase progressively with increasing severity. Highest AST and ALT observed in our study was 764 and 926 U/L respectively. AST and ALT of 1445 U/L and 7590 U/L respectively was reported in a Chinese retrospective study. [20] ALP was elevated in 37.9% cases in our study while ALP was elevated in 20% cases in a similar study. [16] 16.5% cases were diabetic and 15.4% cases were hypertensive in our study compared to 5.7% cases of diabetes and 14.3% cases of hypertension in a previous report. [15] . Liver injury was seen in 64.3% cases of hypertension and 73.3% cases of diabetes in our study. In our centre, patients were mainly administered with antibiotics (Ceftriaxone, Azithromycin), antivirals (Favipiravir, Remdesivir), Low molecular weight heparin, steroids, symptomatic management with anti-pyretic (paracetamol) and oxygen support via oxygen mask, high flow nasal cannula and mechanical ventilatory support. Fan et al suggested the use of Lopinavir-Ritonavir in covid-19 patients following admission as a possible cause for J o u r n a l P r e -p r o o f 8 liver dysfunction [18] which was not the case in our study. At present, there is no standardised definition or criteria for covid-19 related liver injury. In-depth study and further studies are warranted to define covid-19induced liver injury to guide proper care and management.

Our study has some limitations. Firstly, it is a single centre, cross-sectional study. The levels of biochemical parameters were recorded at the time of admission. Serial measurements can help to draw better conclusions. Secondly, GGT and albumin levels were not investigated in our study. Thirdly, the association of other co-morbidities like diabetes, hypertension, coronary artery disease on the severity and prognosis of liver injury was not investigated. J o u r n a l P r e -p r o o f 

World Health Organization. Pneumonia of unknown cause -China

World Health Organization. WHO Director-General's remarks at the media briefing on 2019-nCoV on 11

COVID-19: Transmission, prevention, and potential therapeutic opportunities

Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures

Central nervous system manifestations of COVID-19: A systematic review

ST-Elevation Myocardial Infarction in Patients With COVID-19: Clinical and Angiographic Outcomes

Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review

Review article: COVID-19 and liver disease-what we know on 1st

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Postmortem Examination of Patients With COVID-19

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

Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience. medRxiv

Pattern of liver injury in adult patients with COVID-19: a retrospective analysis of 105 patients

Prevalence of Abnormal LiverFunction Tests in COVID-19 Patients at a Tertiary Care Centre

Epidemiology Working Group for NCIP Epidemic Response, Chinese Center for Disease Control and Prevention

Clinical Features of COVID-19-Related Liver Functional Abnormality

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

COVID-19: Abnormal liver function tests

Clinical characteristics of 2019 novel coronavirus infection in China

J o u r n a l P r e -p r o o f