Impact of Hepatic Dysfunction on Mortality among Coronavirus Disease 2019 Patients: An Inhospital Observational Study

Abstract

Background:

In the modern-day pandemic of coronavirus disease 2019 (COVID-19), gastrointestinal (GI) and hepatic manifestations and associated comorbidities are recognized to have poor prognostication in patients with COVID-19. In our present study, we aim to study the frequency of GI manifestations and hepatic dysfunction and to assess for prognostication among hospitalized patients of COVID-19.

Materials and Methods:

A retrospective cross-sectional study of hospitalized patients of COVID-19 in a tertiary teaching hospital in South India. Clinical data regarding their GI symptoms and hepatic dysfunction, associated comorbidities, severity of disease, and clinical outcome were recorded.

Results:

A total of 1006 patients were included in the study. Severe COVID-19 was seen in 23.3% of the patients, mortality rate of 14.5%. GI manifestations were seen in 17.7% of all, the most common being vomiting (7.1%) and abdominal pain (6.9%). Hepatic dysfunction is seen in 46.5% of COVID-19 patients, which was associated with severity and mortality. However, GI manifestations were not associated with severity and mortality.

Conclusion:

The occurrence of GI manifestations was common. Hepatic dysfunction was seen more frequently among COVID-19 patients and associated with severity and mortality.

INTRODUCTION

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of August 31, 2021, 217 million cases and 4.5 million deaths worldwide were attributed to the disease, with 32 million cases with 0.43 million deaths[1] recorded in India. The clinical spectrum of COVID-19 disease is wide, ranging from asymptomatic infection to severe pneumonia, respiratory failure, and death. COVID-19 has been reported to be severe in 14% and critical in 5% of the affected patients.[2]

Although respiratory symptoms predominate in CoV2 infections, gastrointestinal (GI) manifestations were also seen. GI manifestations were reported in up to 15% of individuals with COVID-19 and the affected patients tend to have poorer disease outcomes.[3] Deranged liver functions were recorded in 19% of the infected patients with a higher risk of progression to severe disease in a recent meta-analysis.[3] With this background, we aim to study the prevalence of GI and liver abnormalities among COVID-19 patients who were admitted to a tertiary care center in South India and its effect on the outcome.

MATERIALS AND METHODS

This is a retrospective cross-sectional study conducted in a cohort of COVID-19 patients who were admitted to a tertiary care center in India. The study was initiated after Institutional Ethical Committee approval (IEC 489-2021). We collected data of patients who were admitted to the hospital with a laboratory-confirmed diagnosis of COVID-19 from mid of July 2020 to September 2020. Patients were excluded if they were younger than 18 years, who were not admitted but managed on an ambulatory basis, pregnant patients, and those with missing data on the outcome. Data were collected in a predesigned proforma.

All the suspected patients underwent nasopharyngeal and/or oropharyngeal swabs for SARS-CoV-2 RNA by reverse transcriptase–polymerase chain reaction and those who tested positive were diagnosed as COVID-19. All patients’ details related to demographics, clinical symptoms, comorbidities, laboratory parameters at the time of admission, and outcomes in the form of discharge or mortality were collected. Demographic variables including age and sex, comorbidities including the history of diabetes, hypertension (HTN), coronary artery disease, chronic obstructive pulmonary disease (COPD), chronic liver disease, and chronic kidney disease (CKD) were recorded. Initial laboratory data including complete blood counts, serum creatinine, liver functions including total bilirubin, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), prothrombin time, and international normalized ratio were recorded. All the patients with deranged liver function tests underwent hepatitis B surface antigen and anti-hepatitis C virus testing. The severity of COVID-19 was determined based on the revised national guidelines on clinical management of SARS-CoV-2 infection given by the Ministry of Health and Family Welfare, Government of India. The patients were managed with supportive care and specific protocols created by the hospital’s COVID-19 management guidelines committee by the Government of India.

Values of liver functions vary among different published studies and countries. The cutoff values for total bilirubin, AST, ALT, and ALP were taken as 1.2 mg/dL, 40 IU/L, 40 IU/L, and 130 U/L, respectively, as per local laboratory standards. Albumin levels below 3.5 g/dL were considered abnormal. According to ACG guidelines, AST and ALT abnormalities were defined as borderline elevation if the values were <2 times the upper limit of normal (ULN), mild elevation as two to five times the ULN, moderate elevation as five to ten times the ULN, and severe elevation as levels more than 10 times the ULN. In addition, all serum bilirubin and ALP values above the ULN were considered to be abnormal.

Categorical variables were presented as percentages, whereas continuous variables were presented as mean (standard deviation) or as median (interquartile range). Comparisons between proportions were performed using the Chi-square test and continuous variables using the student t-test and Mann–Whitney nonparametric U-test. For all tests, P < 0.05 was considered statistically significant. The analysis was performed using SPSS software (IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY, USA: IBM Corp).

RESULTS

One thousand and eighty-five patients were admitted with a diagnosis of COVID-19 during the study period, of which a total of 1006 patients were included in the study. Others were excluded as they had incomplete or missing data, were pregnant patients, or were <18 years of age. The male-to-female ratio is 1.67 with a mean age of 50.07 ± 18.24 years. Comorbidities were seen in 548 (54.5%) patients. Comorbidities were more prevalent among male patients, i.e., 63% as compared to 40.75% among female patients.

Based on the disease severity, severe cases were seen in 23.3% (n = 234), while mild and moderately symptomatic cases were seen in 41.5% (n = 417) and 17.7% (n = 178) of the patients, and 17.81% (n = 177) were asymptomatic for COVID-19.

Diabetes mellitus (DM) followed by HTN were the most common comorbidities (36.1% and 34.5%, respectively), while ischemic cardiac disease was seen in 13.4% of the patients. COPD, CKD, and chronic liver disease were seen in 4.4%, 10.2%, and 2.1% of the patients, respectively, while the cerebrovascular event was noted in 3.9% of the patients. About 22.8% and 16.9% of the patients had one and two associated comorbidities, respectively, while 14.8% of them had three or more comorbidities.

The mortality rate among our tertiary care center patients was 14.5% (n = 146). The mortality rate was high among severe cases at 52.56% (123 patients out of 234) while nonsevere patients had a mortality rate of 2.97% (23 patients out of 772 patients). There was no significant difference in mortality among females versus males (12.03% vs. 16.13%).

The presence of comorbidity was associated with the severity of the disease (P < 0.001). About 77.66% of moderate–severe COVID-19 patients and 38.38% of mild and asymptomatic patients had associated comorbidities. Among various comorbidities, severe disease was seen in 37.74%, 37.17%, and 38.51% of patients with DM, HTN, and ischemic heart disease (IHD), respectively. About 42.8% of patients with cirrhosis of the liver had the severe disease.

The presence of any comorbidity was associated with mortality (P < 0.001). Among the various comorbid illnesses, cirrhosis of the liver had a mortality rate of 38.09% and CKD at 31.06%. Mortality among patients with DM, HTN, and IHD patients was 22.86, 23.34, and 28.8%, respectively. Cerebrovascular accident and COPD had mortality rates of 28.2% and 13.63%, respectively. Those with associated comorbid illness had a mortality rate of 20.22% compared to those without at 7.07% (P < 0.001). Those with one comorbid illness had a mortality rate of 12.55%, while those with two comorbidities at 21.08% and with three or more comorbidities had a mortality rate of 31.03%.

GI manifestations at presentation were seen in 17.7% of patients. Vomiting (7.1%) and abdominal pain (6.9%) followed by diarrhea (6%) were the most common GI symptoms. Nausea and jaundice were seen in 1.1% and 0.9% of patients, respectively. The presence of GI symptoms was not predictive of the outcome, either the mortality or severity of COVID-19 (Chi-square test: P > 0.05).

Deranged liver functions were seen in 46.5% of all COVID-19 patients. The most common deranged liver function was elevated AST levels seen in 31.9% of patients followed by elevated ALT levels (25%). High ALP was seen in 13.7% of patients while bilirubin levels were elevated in 13.7% of patients. Moderate-to-severe elevation of ALT and AST were seen in 1.5% and 2.4% of patients, respectively, while the borderline-mild elevation of ALT and AST were noted in 23.5% and 29.5% of all patients, respectively. The presence of deranged liver functions was predictive of mortality and severity (Fisher’s exact test, P < 0.001). Among the survivors, 16.9% of survivors had GI symptoms compared to 21.83% among nonsurvivors. While abnormal liver functions were seen in 43.34% of survivors when compared to 67.6% among nonsurvivors (P < 0.0001).

DISCUSSION

Although SARS-CoV-2 primarily causes respiratory symptoms, extrapulmonary manifestations involving almost all organ systems have been described. GI and liver manifestations are also seen frequently as GI epithelial cells, liver cells, and bile canalicular duct cells express angiotensin-converting enzyme 2 (ACE2), which acts as a primary receptor of SARS-CoV-2.[4] In this study, we included more than a thousand patients who were diagnosed and hospitalized with COVID-19 and identified their GI manifestations during the initial presentation.

Specific host–virus interactions that enhance the cell entry efficacy include high binding affinity of the receptor-binding domain (RBD) of the spike protein, evasion of the host immune system by reduced exposure of the RBD to the outside, and furin protease activation of the virus before entry into host cells reducing its dependence on target cell proteases such as transmembrane protease and serine 2.[5] In addition to respiratory transmission in the form of droplets, the presence of fecal SARS-CoV-2 viral RNA has been reported.[6] The two main mechanisms involved in the causation of GI COVID-19 manifestations include the direct effect of viral cytopathic damage on the mucosa and an indirect effect due to a systemic cytokine storm.

We have noted that 17.7% of those infected with COVID-19 had GI manifestations at presentation. The most frequent complaints were vomiting (7.1%), abdominal pain (6.9%), and diarrhea (6%). Initial reports from the epicenter of the pandemic in Wuhan, China, noted that GI symptoms including vomiting and diarrhea were seen in 3.8%–5% of the patients.[7,8,9] Outside of Wuhan in China, any GI symptom was reported in 11.4% of COVID-19-infected patients.[10] Our study findings were also similar to another recent meta-analysis where the most frequent GI symptoms noted were diarrhea, nausea, and abdominal pain in up to 5.6%–16.5%.[11,12] Another study conducted in India concluded that diarrhea and abdominal pain were present in 8.7% and 2.7% of patients, respectively.[13] Finally, a recent study from North India published that 10.3% of their patients suffered from GI symptoms secondary to COVID-19 infection.[14]

The mortality rate among our tertiary care center patients was 14.5%. This is similar to other published reports from India[15] and a recent meta-analysis.[16] Fatal complications of COVID-19 include acute respiratory distress syndrome leading to respiratory failure, cardiac failure, renal failure, and multi-organ failure.[17] Although the frequency of GI symptoms was higher among the mortality group (21.83%) than those with survivors (16.9%), it was not statistically significant. Conflicting studies demonstrate the association of GI symptoms with severity. Many studies, including a meta-analysis[11,18] show that it has no impact on mortality or severity, while few studies, including a community-based study from North India that showed patients with GI symptoms, had severe, critical illness with a fatal outcome than those without.[14,19,20] As we have evaluated GI symptoms at presentation to the hospital, antibiotics and other drugs taken by patients before hospitalization could not be ruled out in the causation of GI symptoms.

Comorbidities were present in 54.5% of the patients, and as expected, the presence of any comorbidity was associated with increased mortality compared to those without. To the best of our knowledge, there were no cohort studies from India comparing the inhospital mortality rates among various comorbidities. The patients with chronic liver disease had the highest mortality at 38.09%. In a multicentric study done in Asia, Italy, and worldwide, the mortality rate among cirrhotic patients with COVID-19 ranged from 16% to 34%.[21,22,23] Ours was similar to a study from India, which showed that mortality was 42.3% among cirrhotics.[24]

The SARS-CoV-2 virus can cause liver injury directly by binding to the ACE2 receptors on bile ducts. Liver injury can also occur due to hypoxia or ischemic hepatitis during illness, in addition to various therapeutic drugs used, including remdesivir or tocilizumab. We have observed abnormal liver functions among 46.5% of patients, the most common being transaminases (31.9% and 25% of patients with elevated AST and ALT, respectively) with high mortality among patients with deranged liver functions. As AST is found in other tissues in addition to ALT, AST elevation was more common than ALT elevation, which is specific to the liver. Abnormal liver functions were associated with mortality (43.34% among survivors vs. 67.6% among nonsurvivors). This is similar to other studies, which noted that more than half of the patients have elevated transaminases and these patients had severe disease and mortality.[13,25] Few meta-analyses noted that deranged liver functions were associated with high severity and mortality.[3,26]

Our study’s main strength is the large sample size. The few limitations of our study include its retrospective nature and selection bias that could not be ruled out. Due to the pandemic restrictions and hospital infection protocols, ultrasound abdomen was not done for our patient population.

CONCLUSION

GI manifestations and deranged liver functions were seen frequently among our COVID-19 patients. The presence of abnormal liver functions or the presence of cirrhosis of the liver was associated with poor outcomes in our study.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.