COVID-19 and Hepatic Encephalopathy: A Narrative Review

The 2019 novel coronavirus (COVID-19) has been known as a highly pandemic virus that is characterized by a severe multiorgan pathology. Generally, cardio-respiratory complications are the dominant manifestations in patients infected with COVID-19. Since the coronavirus targets angiotensin-converting enzyme (ACE) receptors, however, the virus is also likely to exhibit multiorgan complications. Some retrospective cohorts as well as case studies have shown varying degrees of increased alanine transaminase (ALT)/aspartate transaminase (AST) in COVID-19 infections. A limited number of histopathological studies examining the liver have also reported an acute portal necrosis of this organ. Some other studies investigating the patients with COVID-19 have documented an acute hepatic encephalopathy with altered mental status. Beyond doubt, having a greater awareness of these complications positively contributes to timely and effective management and treatment of the patients. The present review article, therefore, aimed to highlight the consequences of developing hepatic encephalopathy for patients with COVID-19, its possible multifaceted mechanisms, and the management of neurological complications in these infected patients.

The Mechanisms of Hepatic Encephalopathy COVID-19 virus may directly or indirectly affect the nervous system through various pathways, and many studies have demonstrated that the virus is capable of reaching the CNS through blood circulation, nerve fibers, or direct invasion via the olfactory bulb (16). It is noteworthy that an indirect invasion to the CNS may be carried out through hypoxemia, immune-mediated injury, or multi-organ involvement with a potential for CNS complications (10,17). It is noteworthy that in the COVID-19 infection, the liver is the second organ affected after the lungs, which can lead to hepatic encephalopathy (18).

Angiotensin Converting Enzyme 2 Receptor Role to Entrance COVID-19 Into Liver
The mechanism that indicates organ-specific affinity for COVID-19 is associated with ACE2 receptors. There is evidence for the presence of ACE2 receptors in the brain -in nerve and glial cells, in particular -as well as in the liver; in fact, a strong relationship has been identified between COVID-19 and these receptors causing the infection (16,18).
Liver damage is one of the complications that may occur in the patients infected with coronavirus. This complication might be caused by a direct damage to liver cells due to the spread of infectious virus. Previous studies have demonstrated that about 2 to 10 percent of the patients with COVID-19 are also afflicted with diarrhea, and SARS-CoV-2 RNA can be found in their blood and stool samples (19). This finding suggests that the virus is likely present in the liver cells. SARS-CoV-2 and SARS-CoV enter the target cells via binding to the ACE2 receptor (20), where the virus multiplies and eventually infects the upper respiratory system as well as the lung tissue. Subsequently, clinical signs and symptoms begin in the patient. The pathological evidence from infected patients is indicative of the presence of the virus in liver tissue; however, the virus titer in liver tissue has been reported to be relatively low (21). It should be noted that the virus particles in liver tissue have not been measurable in patients infected with MERS (22). Studies examining 56 patients infected with COVID-19 during hospitalization period showed that only one patient (1.8%) had increased alkaline phosphatase levels (23). However, pathological finding from the liver tissue of a patient who had died of COVID-19 confirmed the absence of viral compounds in the liver (24).

Immune-Mediated Encephalopathy Followed Liver Damage in Infected Patient With COVID-19
Immune-mediated inflammation, like cytokine storms and hypoxia associated with respiratory failure, may also contribute to the development of liver damage or even lead to liver failure in patients with severe COVID-19 (23). Severe viral infections cause systemic inflammatory response syndrome (SIRS). Studies have confirmed that severe pneumonia could result in SIRS via CoVs infection (25). In this regard, previous findings have suggested the early use of anti-inflammatory drugs as a method to prevent immune injury as well as decrease the risk of CNS damage in patients with COVID-19 (26). In addition, many studies have reported a high mortality rate due to viral infections caused by both SARS-CoV and COVID-19 viruses, since these diseases multiple organ failure following SIRS caused by the virus or SIRS-like immune disorders (27,28). This point is wellsupported by the fact that the level of interleukin (IL)-6 as an important factor of the cytokine storm family is directly associated with the severity of COVID-19 disease (29). According to another study, hypercytokinemia was detected in COVID-19 patients (30).
An important feature of the CoVs virus is its potency to infect macrophages, astrocytes, and microglia in the CNS. Studies have shown that these viruses are able to hmj.hums.ac.ir http activate glial cells and, thus, lead to the production of proinflammatory cytokines from these cells (31). Another in vitro study on glial cells following CoVs infection found a significant increase in inflammatory agents like IL-6, IL-15, IL-12, and TNF-α in these cells. (32). Given the high homology between COVID-19 and SARS-CoV, it is important to consider the neurological manifestations previously confirmed for other COVs, particularly in elderly cases who are afflicted with COVID-19 and are prone to neurological manifestations.

Liver Injury of COVID-19 That Can Cause Hepatic Encephalopathy
In severe cases of COVID-19, respiratory distress or hypoxia occurs nearly seven days after the onset of the disease, and these complications eventually lead to acute respiratory distress syndrome, metabolic acidosis, septic shock, and even death (3). Recent studies have shown that the rate of liver damage varies from 14.8 to 53 percent, which is mainly due to elevated alanine transaminase (ALT)/ aspartate transaminase (AST) levels as well as bilirubin levels (3,15,20,(33)(34)(35). Serum albumin levels are also reduced in patients with high disease severity (26.3-30.9 g/L) (36). Some study results have indicated that the possibility of liver damage in severe cases of COVID-19 is significantly higher than that in mild cases (3,33). As for the fatal cases of COVID-19, several studies have reported that 58.06% (37) and 78% (38) of the patients sustain liver damage. A recent research has also shown that serum ALT and AST levels in a severe COVID-19 patient increases to 7590 U/L and 1445 U/L, respectively (36). To date, few studies have examined the mechanism of COVID-19-related liver damage. It has been confirmed that SARS-CoV-2, similar to SARS-CoV, uses ACE2 as a receptor to enter liver tissue (37). A previous study has also confirmed that liver cells and bile duct cells express ACE2 (39). However, the expression of the ACE2 receptor in bile duct cells is much higher than that in hepatocytes, although it is lower in type 2 alveolar cells in the lung. Bile duct epithelial cells have been determined to be the most important cells in regenerating the liver tissue and inducing the immune reactions (40). These findings suggest that the liver damage in COVID-19 patients may be secondary to the bile duct cell damage. In severe COVID-19 disease, on the other hand, an inflammatory cytokine storm occurs (41); however, further studies are needed to address this factor in liver damage. The results from postmortem biopsy in COVID-19 patients, microvascular steatosis, as well as mild lobular and portal activity have demonstrated that these manifestation could be due to SARS-CoV-2 infection or liver damage caused by drug toxicity (42). It is now a common knowledge that COVID-19 is treated with a wide range of antibiotics, antivirals, and steroids. All these drugs may have potential to exert positive effects on liver damage; however, the efficacy of the given drugs has not yet been medically confirmed (43). In effect, a recent report has suggested that liver damage in COVID-19 cases may be caused by lopinavir/ritonavir which is used as an antiviral to treat SARS-CoV-2 infection (34).

The Evidences of Hepatic Encephalopathy in Patient With COVID-19 Infection
Hepatic encephalopathy is known as a serious neuropsychiatric syndrome, which can occur as the result of an acute inflammation (13). Studies have revealed that the disease occurs in cases of acute liver failure following a viral infection. Some other studies have also demonstrated that hepatic encephalopathy may afflict the patients infected with SARS-CoV-2 (11,44). The first case of hepatic encephalopathy was identified in a patient with COVID-19 at Ditan Hospital in Beijing, by genomic sequencing of the virus in a cerebrospinal fluid sample (45). A 55-year-old woman with COVID-19 was reported to have been diagnosed with hepatic encephalopathy based on her clinical history, laboratory tests, and radiology. The patient also showed neurological symptoms including anxiety, delirium, confusion, and seizures. Significant increases were also detected in elevated levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and plasma ammonia, as well as in inflammatory factors such as ILs 6 and 10 (46). Another case proving the association of COVID-19 with hepatic encephalopathy was a 32-years-old African American male patient diagnosed with COVID-19 by analyzing the reverse transcription polymerase chain reaction (RT-PCR) as well as the qualitative IgM, computerized tomography (CT) of his chest and clinical symptom. In this patient, moreover, increases were observed in the levels of C-reactive protein, IL 6, ferritin, and D-dimer. Reports from the fourth day of his illness state showed progress in behavioral and cognitive dysfunction, and the Glasgow Coma Scale was found to be 13/15. The brain CT confirmed the cerebral edema as well as the symmetric hypoattenuation within the medial thalami signs of intracerebral hemorrhage (11).
An Iranian boy aged 14-year-old was significantly reported to present with an abdominal protrusion, lower extremities pitting edema, icter, and weight gain. He had no history of fever, nausea, vomiting, oliguria, myalgia, and dyspnea, although he was in contact with his family members with cough. His chest radiography revealed diffuse haziness through the left lung field. Bilateral, multifocal, and subpleural ground-glass opacity with mild pleural effusion was detected during his spiral chest CT scan without contrast, which was strongly suggestive of COVID-19. His nasopharyngeal swab sample RT-PCR confirmed the diagnosis of COVID-19 pneumonia, and the serial nasopharyngeal sample test for COVID-19 was found positive for three consecutive weeks. The results of several abdominal paracenteses were transudative and clear. There was every indication that the patient needed hmj.hums.ac.ir http an emergency liver transplantation, and his condition subsequently worsened despite an initial improvement. He gradually developed encephalopathy with mood and mental status changes such as day time sleeping, lethargy, tremor, and respiratory distress. Unfortunately, the patient died after 18 days of hospitalization with features of refractory pulmonary hemorrhage (44).

Evaluation and Management of Hepatic Encephalopathy in Patients Infected With COVID-19
Since COVID-19 is a very contagious and serious virus with a critical incubation period, it is necessary to take preventive measures, establish early diagnosis, and provide timely treatment in order for properly dealing with it. To date, the most standard diagnostic method for confirming COVID-19 infection has been nucleic acid amplification tests. Due to the high probability of error occurrence in this method, however, the negative results of this test cannot rule out the probability of infection and, therefore, repeated tests may be required (47). An important point to consider is that the manifestations of this disease in COVID-19-infected patients vary greatly from person to person. Similarly, most studies have identified respiratory symptoms as the primary complications in patients. Although, there is ample finding that a limited number of patients have other manifestations, including the neurological complications that were fully described above, which can occur following acute liver failure (6,8) . Importantly, neurological involvement is more common in patients with severe degree of infections, which may cause cerebral hemorrhage, ischemic stroke, and even death (8,48,49). In addition, a significant increase in inflammatory factors is an important cause of clinical exacerbation of the disease (50). It is noteworthy that neurological disorders may be nonspecific in the early stages of COVID-19 infection, which can lead to misdiagnosis and delayed treatment. Therefore, careful physical examination, medical history review, as well as imaging take on added importance at the time of diagnosing liver failure and subsequent hepatic encephalopathy in order for properly managing and timely treating the patients (51).

Conclusion
Overall, the available evidence suggested that the CNS was sensitive to COVID-19. According to our findings, most cases infected with COVID-19 may have shown minor and nonspecific neurological complications at the onset of the disease, leading to misdiagnosis and delayed treatment. Although neurological involvement had been previously reported more frequently in patients with severe infections, it was determined that neurological manifestations were also likely to occur among these patients due to liver failure. Given the scant evidence existed for neurologic presentation due to liver injury in patients infected with COVID-19, it was recommended that further studies be conducted to elucidate the neurobiology and mechanisms of hepatic encephalopathy, prevent its occurrence, as well as manage and treat it timely.