COVID-19: a viewpoint from hepatic perspective

Introduction

A cluster of patients with pneumonia of unknown cause were reported in Wuhan, China during last months of 2019. Further molecular techniques such as real time (RT) PCR and next generation sequencing (NGS) confirmed cases as novel Betacoronavirus [1]. It became a pandemic spread all over China in less than 30 days. The few cases of Wuhan in 2019 have now become more of an endemic spread all around the globe. 72,314 people were infected by the disease in China on 2nd week of February itself [2]. Coronavirus is a part of larger family of viruses known to cause a constellation of symptoms including fever, common cold and severe acute respiratory syndrome (SARS). The latest outbreak has been by virus named 2019-nCoV which was later renamed as COVID-19 by WHO [3]. On the same day, COVID-19 was designated as severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) based on its phylogenetic analysis which was published by the Coronavirus Study Group (CSG) of the International Committee on Virus Taxonomy [4]. However, a group of virologists has suggested renaming SARS-CoV-2 as human Coronavirus 2019 (HCoV-19). Such a name distinguishes the virus from SARS-CoV and keeps it consistent with the WHO name of the disease it causes, i.e., COVID-19 [5]. The name officially designated was SARS-CoV-2, however some scientists have suggested to use a different name for it which could have confused public and the etiologic agent name was not constant. Finally, the name of disease being chosen as “COVID-19” by WHO [6]. Now the worldwide cases have crossed 19 million with more than half a million deaths and cases in India has also crossed two million case mark despite lockdown and restrictions from 4 months. The death toll in country have crossed 20 thousand. Hypertension followed by Diabetes [7], IHD, obesity in young [8] are the risk factor. The probability of getting infection increases with age and coagulative disorders [9].

Clinical features of SARS-CoV-2 infection

In general, both animals and humans are affected by Coronavirus. Multiple events of mutation during infection among animals can make virus pathogenic for humans. There can be cases where the virus first affects animals and then turns into a new virus that affects humans. COVID-19 infection can lead to serious complication notebly pneumonia, which can be life threatening. With the already established phylogenic relation of SARS-CoV-2 with severe acute respiratory syndrome-like (SARS-like) bat viruses, it can be inferred that the possible primary reservoir could be bat. COVID-19 virus is transmitted mainly through droplets generated while an infected person coughs, sneezes, or exhales. The droplets being too heavy to hang in air, settles down fast and thereafter gets transmitted through smog generated during cleaning, spreading and infection.

Moreover, Infection can also be transmitted by touching nose, mouth, and eyes after touching contaminated surfaces [10]. Studies throughout the world has demonstrated a number of symptoms being associated with COVID-19, ranging from mild to severe. COVID pathogenicity takes around 2–14 days after infection of Virus. The disease usually presents with fever, running nose, fatigue, shortness of breath, headache, loss of taste and smell sensation and diarrhea or vomiting. Out of these symptoms high grade fever alone is commonest along with sore throat and cough. Dyspnea and diarrhea are also found in significant number. Rhinorrhea is less common, while others are moderate in occurrence. An abnormal chest radiograph finding or lung crepitation is found in significant number of patients. Lymphopenia is also found in various studies pointing to 30–50 percent, while kidney function remains mostly normal. There is elevated CRP among many of the patients [11], [12], [13].

COVID-19’s complications

The most frequent complication of COVID-19 is ARDS (Figure 1) [14]. The post mortem findings in such patient are usually hyaline membrane in lungs. The patient may survive ARDS and candie of shock, acute kidney injury, cardiac arrhythmia. In such cases hyaline membrane would often not be found but scar in the site of lung lesion can speculate previous episode of respiratory distress. Superimposed bacterial pneumonia is another complication which is most virulent. A portion of COVID-19 patient particularly those with ARDS have a procoagulant profile which further makes them prone to complications like pulmonary embolism [15]. The risk of pulmonary embolism also increases with hospitalization. If anticoagulants like heparin are started early and prudently then late complication like DIC can also be prevented. Lymphocytopenia and thrombocytopenia are other complications seen in these patients [16]. Neurologic symptoms and rhabdomyolysis are very rare complications and are not often described. Physicians however should be aware that encephalitis can occur in the acute setting or during hospitalization. Alcoholism and other infection makes patients prone to rhabdomyolysis which can lead to acute kidney injury [17, 18].

Figure 1:

Various complications of COVID-19.

Laboratory findings in COVID-19

The most common laboratory finding among COVID patients is lymphopenia, which presents in almost 83% of patients. Other common laboratory observations are high levels of liver enzymes such as serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase along with elevated inflammatory markers namely, serum ferritin and C-reactive protein (CRP). Moreover, higher mortality has been associated with elevated D-dimer and lymphopenia. High levels of procalcitonin has been detected in ICU patients, however levels were normal in non-serious patients. Cytokine storm with raised inflammatory marker suggest potential immune dysregulation in the disease.

On radiological examination chest radiograph typically demonstrated bilateral air-space consolidation, however in milder cases films were normal. RT-PCR is more sensitive than Chest radiograph and CT for diagnosing COVID-19. However, Chest computed tomography (CT) scans from patients of COVID-19 demonstrated nonspecific peripheral ground glass opacities, which was common with many of other infections. Moreover, the diagnostic value of CT was subject dependent and hence had limited clinical implications. Hence, case to case variability among COVID patients and limited overall diagnostic capabilities make chest radiography or CT scanning unsuitable to consider as the diagnostic test. In the same line, American College of Radiology also does not consider CT scanning as first line test or screening test to diagnose COVID-19. However, in almost half of patients CT scan has been documented as abnormal even before positive RT-PCR result [19]. Severe patients with pneumonia often demonstrated fever, leukocytosis, neutrophilia, high C-Reactive Protein level, D-dimer level, alanine aminotransferase activity, aspartate amino transferase activity, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase activity and creatine kinase activity. Lower lymphocyte count, lymphocyte percentage and total protein level were also found in multiple patients. Adverse events were typically associated in patients with higher creatinine level, male, and lower platelet count and those in age below 40 or above 60 years, [20, 21].

SARS-CoV-2 infection

The infection was first described as Avian infectious bronchitis among newborn chicks in 1931 (Fred Beaudette and Charles Hudson). Then Almeida and Tyrell, along with six other colleagues, documented in Nature in 1968 that the same group of viruses not only caused avian bronchitis but also upper respiratory tract diseases in humans and murine hepatitis. This was the first recorded instance of the term “Coronaviruses” with human infection. Though the term “corona” has multiple meanings, but it was meant as sun while naming for corona virus. Moreover, they compared the outer projections of virus even with the solar corona [22]. One of the predominant mechanism of pathogenesis of COVID-19 is its attachment with angiotensin-converting enzyme receptor, present on cholangiocytes of liver leading to excretion of virus in faeces. However, it is not known whether infection of cholangiocytes is a direct one or an infection secondary to direct infection to liver. Secondly, liver injury could be a result of abnormal immune response with systematic inflammation and release of cytokines namely IL-6, causing direct cytopathic damage to the liver. Thirdly, liver injury could be due to drug toxicity due to prolonged administration of antibiotics, antivirals and ant antipyretic drugs e.g., non-steroidal anti-inflammatory drugs. Liver biopsies of patients demonstrated portal and lobular inflammatory infiltrates along with microvacuolar stenosis [23, 24].

Pathological basis of complications in COVID-19

Spike glycoproteins, or peplomers which give corona-like appearance of Coronaviruses are the major organ required for host attachment and entry in host cells. Spike has two different subunits, which are S1 allowing binding to the surface of host cells, and S2 helping in fusion to cell membrane. As shown in Figure 2, the receptor found on cell membrane for both SARS-CoV-1 and SARS-CoV-2 is a type of angiotensin converting enzyme, ACE-2, which is different from the conventional enzyme inhibited by Ramipril and enalapril. Concisely, the S1 subunit of the viral spike binds directly with the ACE-2 enzyme present on the cell membrane surface. Further, TMPRSS2, a host transmembrane serine protease activates the spike part and cleaves ACE-2. Moreover, TMPRSS2 also acts on the S2 subunit, enabling virus to fuse with the host cell membrane and allowing virus entry inside the cell. Once inside, virus is released from endosome by the acidification caused by intracellular cysteine protease, mainly cathepsin [25, 26].

Figure 2:

Interactions of SARS-CoV-2 with ACE receptor of host cell.

Anti-viral treatment for COVID-19

COVID-19 and hepatic pathology

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has become a pandemic spread all over globe and is considered a major threat to human life. Approximately, one third of hospitalized patients of SARS-CoV-2 infection has deranged liver enzymes and requires longer hospital stay. Moreover, a significant proportion of patients with abnormal liver function required antiviral treatment in the form of lopinavir/ritonavir [27]. Furthermore, patients of chronic liver disease (CLD) has much more proportions of deranged liver tests, although its clinical significance is yet to be established. Liver impairment has been frequently reported as a common manifestation, although its clinical significance is still unclear, particularly in patients with underlying chronic liver disease (CLD). Abnormal liver function tests during the course of COVID-19 are common, though clinically significant liver injury is rare. Deranged liver function test, most notably mildly elevated transaminases are most commonly found in COVID-19. With the current information available liver pathology is result of many factors such as direct impact of virus, drug toxicity or associated inflammation and cytokine storm. COVID-19 has least impact on children, hence any liver enzyme derangement if detected should be evaluated for some other disease, most commonly of congenital origin. Chronic liver diseases patients are not at higher risk of infection, though once infected they are more prone for complications such as non-alcoholic fatty liver disease, cirrhosis, and autoimmune liver diseases. Liver transplantation is another risk for COVID-19 related liver injuries. Most of the initial liver injuries of COVID-19 can be detected by abnormal liver biochemistries. With the documented risk of hepatic injury and its complications and with limited management of moderate-to-severe disease, it can be inferred that monitoring hepatic enzymes can be an crucial step in management of COVID-19 [23]. Moreover, even if laboratory parameters deteriorate, it suggests disease progression, often contributed by inflammation, cytokine storm, cardiac dysfunction ischemia, sepsis and drug toxicity. Further research is needed to understand the COVID-19 pathology and measures to avoid complications.

With the continuing pandemic, more and more drugs are being investigated and are included in treatment regimes of hospitalized patients with COVID-19. Many of these drugs have a well documented risk along with its time course and pattern of liver injury. Remdesivir, an analog inhibitor of viral RNA polymerase, which was been recently approved by US Food and Drug Administration [FDA] for emergency use under limited situations is experiencing growing use in COVID-19 treatment and has been associated with an alarming 23 percent increase in liver enzymes as per the published reports.

All patients with liver injury are at risk of adverse outcomes from the virus. Therefore, it is advised that all liver patients should attempt to adhere to strict social distancing measures as much as possible which will minimize their chance of exposure to COVID-19. In addition, some people with certain liver conditions are extremely vulnerable and are advised to rigorously follow shielding measures to keep themselves safe. Liver patients who fall into the extremely vulnerable ‘shielding group’ category are people on immunosuppression for a liver transplant or for autoimmune hepatitis (AIH), patients with liver cancer, those who are having immunotherapy or undergoing active chemotherapy or other continuing antibody treatments. Liver injury, which is quite common in COVID-19 patients, may be caused by direct viral infection of bile duct cells or associated functional impairment caused by the use of antiviral drugs. Moreover, many of published data suggest gross loss of liver function among COVID-19 patients as a moderate microvascular steatosis and inflammation in the hepatic lobular portal region. However, direct killing effect of the virus on the liver were limited and are found in few autopsy pathological results. In addition, inflammation associated cytokine storms which are common among severe COVID-19 cases have a doubtful role in direct contribution to liver injury. Available data infer a common point of giving more attention to liver enzymes among COVID-19 patients. Moreover, since underlying liver pathology is also having role in complication of COVID-19 liver pathology, it should be well considered with proper monitoring and evaluation of liver tests among serious patients. Furthermore, a well coordinated research should be conducted to understand the patho-physiological hepatic changes caused by COVID-19. In addition, the possibility of using liver protection treatment should be also considered while treating the primary COVID-19 infection [28].

Future perspectives of liver disease in COVID-19 era

With human infection of COVID-19 being a recent phenomenon, much more research is needed to improve our understanding of disease associated liver injury and treatment plans of hepatic complications. Moreover, as Asia-Pacific region is having a high prevalence of HBV infection, so COVID-19 patients should be well investigated for underlying liver pathology using biochemical and serological tests along with ultra sonogram and other radiological tests. With the emergency authorization of new antiviral drugs for COVID-19, the associated liver toxicity and potential drug–drug interactions should be thoroughly evaluated. Furthermore, research will be required to assess the safety and efficacy of vaccines and the same has to be proved in patients with gross liver disease and recipients of liver transplantation [29].

Vaccine against COVID-19

Before the COVID era, vaccine development programs were evaluated on the basis of just two parameters of the infective agent and the host–agent interaction (incubation period, pathogenesis and relative immunogenicity) were important for vaccine development. For COVID-19 virus, a new parameter is proposed i.e., infectious inoculum intensity. The role of infectious inoculum intensity can be ascertained to the fact that as with the cases of four endemic coronaviruses, the immunity generated after natural infection with the last three human epidemic coronaviruses namely, MERS-CoV, SARS-CoV, and SARS-CoV-2 appear to be short lived [30].

A major breakthrough in the fight against COVID-19 has been achieved now. Several countries have started providing their own indigenous vaccine. The first vaccine developed in world was from Russia. During emergency it was approved while there was no phase III trials nor any results published from phase II and II [31].

Astrazeneca’s Covishield is an adenovirus vector subunit vaccine and has provided encouraging results. Covishield is given in two doses and astrazeneca has found that a lower 1st dose is more efficacious. This could be because of lower first dose produces more memory immune cell activation. Also Covaxin has less stringent storage condition compared to mRNA corona vaccine [32]. One important change due to COVID era is leap of mRNA vaccine as forerunner candidate. These mRNA vaccines cause expression of antigen at the same time regulated and degraded by various pathways. They have their own limitation like stringent storage, relative fragility and inappropriate immune activation [33]. Other future prospects are SputnikV (adenoviral vector Russian vaccine), and Cadila Healthcare’s DNA platform vaccine. At present more than 50 COVID-19 vaccines are in various phases of clinical trial.

India has also achieved the milestone of Indigenous vaccine development. In India the vaccine made available are COVISHIELD, the Oxford–AstraZeneca developed vaccine. This vaccine is also made in India and Bharat Biotech’s COVAXIN [34].

Covaxin is an inactivated killed virus vaccine. However, it has more adverse effect profile compared to Covishield [35]. From Jan 16, 2021, India has begun the world’s largest COVID-19 vaccination drive. This vaccination aims to immunize 30 crore people. The advent and development of indigenous vaccine and other measures related to the COVID 19 pandemic has proved that India has paralleled developed countries in medical development, medical research and infrastructure [36].

COVID-19 vaccines are sure to play the lead role in fight against this disease as well as a major change in our future advent against infectious diseases. However, majority of these vaccines are hurriedly made and even phase three trials of these vaccine including covishield and covaxin has not been published. The role of the vaccines can be more certainly be told with further studies and time only [37].