COVID-19 has become a global public health crisis, with as many as 4 million reported cases of infection, including 84,431 cases in China. Meanwhile, a total of 300 million people in the world have been infected with hepatitis B (HBV) as of March 2018, while the number of HBs-Ag positive people in China is about 80 million [5].
Because the liver is an organ located between the portal vein and the systemic circulation, it is often exposed potentially to viruses, bacteria and inflammatory, sometimes causing liver damage. It is reported that people infected with SARS [6] and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV)[7] have liver damage. A recent epidemiological study in Wuhan showed that of the 99 patients initially infected with 2019-nCoV, 43 had varying degrees of liver dysfunction and ALT or AST were both above the normal range [8]. Another retrospective analysis of patients of COVID-19 with impaired liver function. It is also found that abnormal liver function is common in patients with COVID-19 [9]. The pathological findings of the liver biopsy specimen of the patient who died of COVID-19 were moderate microvesicular steatosis and mild leaflets, with portal vein activity, indicating that SARS-CoV-2 may cause liver damage [10] and viral RNA was also detected in liver tissues in concentrations exceeding viremia [11].
For carriers of hepatitis B, it is unclear whether the SARS-CoV-2 will exacerbate liver function damage or not. Few studies have analyzed the clinical characteristics and outcomes of hepatitis B virus carriers complicated by COVID-19. In this study, we included 72 COVID-19 carriers of hepatitis B. Of these patients, 39 (54.2%) patients had abnormal liver examination results, and 9 (12.50%) patients had liver injury upon admission. With the improvement of COVID-19 treatment, these liver function indicators can gradually return to normal range. Similar to a recent retrospective study based on the characteristics of liver function tests in large hospitals, COVID-19 patients also reported that about half of them had abnormal liver function, and 5% of patients had liver injury upon admission [4]. It is recommended that among the carriers of hepatitis B, the incidence of liver function damage may not increase.
Some studies have shown that patients with abnormal liver function tests will face a higher risk of serious illness [4]. However, in our study, we found that few patients with abnormal liver function at admission exacerbated the disease and liver damage. This finding is consistent with the results of a retrospective study showing that despite common liver function abnormalities in patients with COVID-19, liver damage is not the main feature of COVID-19 and may not have serious clinical consequences [9]. SARS-CoV-2 can directly attack the liver and cause liver dysfunction, but as far as we are concerned, it should be distinguished from the liver function damage caused by the inflammatory factor storm caused by coronavirus, which may be related to the aggravation of the disease.
Two recent studies have shown that angiotensin converting enzyme 2 (ACE2) is a key receptor for SARS-CoV-2 [12] [13]. RNA-seq data in the Human Protein Atlas (HPA) database [14] shows that ACE2 is relatively of low expression in liver and lung which are the main target organs for 2019-nCoV and SARS. A Low-throughput study of ACE2 protein expression in the liver indicates that ACE2 occurs less frequently in cholangiocytes, but not in hepatocytes, Kupffer cells, and endothelial cells [15]. A current study [16] found that coronavirus may directly bind to ACE2-positive cholangiocytes, but not necessarily to hepatocytes, indicating that liver abnormalities in SARS and 2019-nCoV patients may not be caused by hepatocyte damage, probably induced by cholangiocyte dysfunction and other causes, such as drug toxicity and systemic inflammatory response. However, after analyzing the indicators of abnormal liver function at the time of admission, we found that there were not only cholangiocyte dysfunction, but also hepatocyte damage, suggesting that for hepatitis B carriers, in the early stage of COVID-19, SARS-CoV-2 may attack hepatocytes directly as well as cholangiocyte. Therefore, in addition to ACE2,whether there are other SARS-CoV-2 binding sites on hepatocytes, such as CD147 [17], DC-SIGN and l-sign [18] remains to be further clarified, meanwhile, it is not ruled out that the liver dysfunction in these patients is due to coronavirus-induced inflammation or drug toxicity.
In this study, we found sensitive prognostic indicators. The majority of patients had a significant decrease in PA when they were admitted and the PA can gradually increase to normal levels before rehabilitation or discharge. There was a statistically significant difference between admission and discharge (P < 0.0001). PA is an acute reactive protein and mainly present in the blood and cerebrospinal fluid and the plasma half-life is about 1.9 days. PA is synthesized in the liver, when liver damage occurs and intrahepatic synthesis decreases, it can be quickly detected from peripheral blood at an early stage. Therefore, it is considered to be a sensitive indicator of liver function damage and recovery. Our results show that compared with other liver function indicators, the early dynamic changes of PA can be used as a sensitive indicator to judge the prognosis and outcomes of HBV carriers complicated with COVID-19.
Our research also conducted an exploratory analysis of infection-related indicators. We found that the level of SAA increased at the initial stage and will gradually return to normal levels after recovery. SAA is also an acute phase protein and is commonly used to assess the acute response process. There is a similar expression in serum ferritin.
It is well known that there is a dynamic balance between HBV and the host immune system. When the balance is broken, HBV cccDNA is the main substance that replicates with HBV in hepatocytes, which will speed up the replication speed, increase the number of infected cells, and cause HBV reactivation to a certain extent [19]. Therefore, indicators that may impair immune response, such as tumor chemotherapy, immunosuppression or transplantation, may cause HBV reactivation. In patients with COVID-19 is also associated with immune imbalances, while peripheral blood neutrophils are significantly increased and lymphocyte counts are significantly decreased [20] [21] [22]. Therefore, in this study, we tried to explore whether SARS-CoV-2 can cause HBV activation in HBV carriers. Generally, the diagnosis of HBV activation is based on dynamic monitoring of HBV DNA quantitative detection and liver function (especially ALT). However, due to retrospective analysis and limited laboratory test data, there is no direct evidence that SARS-CoV-2 can cause hepatitis B virus reactivation (such as dynamic monitoring of HBV-DNA) [23]. However, from the patient's prognosis and recovery of liver function, SARS-CoV-2 may not directly cause HBV reactivation. In addition, the inflammatory cytokine storm is thought to be related to the severity of the disease, so large doses of glucocorticoids and immunosuppressants will be used during treatment. In this condition, whether it will reactivate HBV and aggravate the occurrence of liver function damage or not remains to be further studied.
Our research also has several limitations. First of all, due to the design of this retrospective study, we have relatively few cases in a single center and not all patients have undergone all laboratory tests, especially liver tests and HBV-DNA quantitative detection. Second, because most patients have a good prognosis and only three patients died in our study, the potential impact of liver abnormalities or injury on mortality can not be assessed. With the emergence of new cases in the world, it is necessary to conduct further large-scale studies among HBV carriers.
In summary, this study describes the clinical features of HBV carriers with COVID-19. We found that more than half of the patients had varying degrees of liver dysfunction in the early stages of pneumonia and these abnormalities may gradually return to normal levels. This phenomenon may be caused by SARS-CoV-2 directly attacking hepatocytes and cholangiocytes. Both PA and SAA are sensitive indicators and can be used to judge the prognosis and outcome of these patients. In addition, in this study, we did not find direct evidence that SARS-CoV-2 may cause hepatitis B virus reactivation. Further research is still needed to explore the impact of SARS-CoV-2 on hepatitis B carriers.