The incidence of liver abnormalities is higher in inactive hepatitis B virus carriers with influenza A infection
iLABMED(2023)
摘要
Influenza A infection leads to a higher incidence of liver injury in HBV carriers than in patients infected with influenza A alone. Moreover, HBV carriers experience earlier onset and greater severity of liver injury than individuals with only influenza A. China is still at a high risk of hepatitis B virus (HBV) infection and has a large number of inactive HBV carriers (ICs) [1]. Chronic hepatitis B viral infection is a global problem, which commonly progresses to liver cirrhosis [2], hepatocellular carcinoma [3], and liver disease-related death [4]. An IC state refers to the presence of hepatitis B surface antigen (HBsAg) in the serum [5, 6] without an elevation in hepatitis B e-antigen (HBeAg) or aminotransferase concentrations in addition to HBV DNA levels <10,000 copies/mL (or 2000 IU/mL). A previous study reported that patients who are ICs may experience a reactivation of infection and develop HBeAg-negative chronic hepatitis B [7, 8], with an annual incidence ranging between 1/100 and 3/100 [9]. Although the natural history of patients with an inactive carrier state is relatively well characterized [10], the incidence of co-infection in ICs and its effect on liver function are unclear. A critical issue in the clinical handling of ICs is the incidence of co-infection in ICs and its effect on liver function. After the influenza A (H1N1) pandemic in 2009–2010 in China, influenza A has been a seasonal epidemic disease [11]. Some studies have reported the occurrence of liver injury during influenza A infection. In 2019, Ciesek and Premkumar reported that the occurrence of influenza A increased the disease progression and disease severity in patients with liver injury [12, 13]. However, the risk of liver injury in ICs who have influenza A has not yet been investigated. Therefore, the present study aimed to determine whether influenza A virus in ICs increases the risk of liver injury in patients without pre-existing liver disease. This retrospective study was conducted between January 1, 2020 and April 1, 2023. This study comprised patients from the Fifth People's Hospital, Wuxi, China and the Third People's Hospital, Shenzhen, China. A total of 103 hospitalized patients with confirmed influenza A and HBV were enrolled in the study. If the RNA of influenza A virus was detected using a relevant test, patients were further evaluated for liver function. Participants who were seronegative for HBeAg had serum levels of HBV DNA <10,000 copies/mL and did not show signs and symptoms of cirrhosis, hepatocellular carcinoma, or any liver function abnormality were classified as ICs. Patients who had no other co-infection other than influenza A infection alone were classified as controls. Serum levels of influenza RNA, HBV DNA and HBV RNA, HBsAg/antibody, hepatitis B core antigen/antibody, HBeAg, and liver biochemistry were measured. We investigated biochemical markers of liver function, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), total bilirubin (TBil), and lactate dehydrogenase (LDH), between patients with ICs and those with influenza A infection alone. Variables are shown as the median and interquartile range (IQR). Biochemical markers were analyzed using the non-parametric t-test with the Mann-Whitney test. We also used the chi-square test to analyze the age composition and sex ratio of the patients. Statistical analyses were performed using the Graphpad Prism Program 8.0. In the present study, 1879 patients with influenza A were recruited. Of these, 1776 patients who did not have a test to identify HBV were excluded from the study. Among the remaining 103 patients, 3 were excluded owing to active HBV, 1 was excluded owing to severe fatty liver, and 8 were excluded owing to cirrhosis. Additionally, five patients receiving immunosuppressants owing to autoimmune hepatitis (n = 3), a tumor (n = 1), or human immunodeficiency virus (n = 1) were excluded. The remaining 86 patients (29 patients with liver injury, 57 patients without liver injury) were included. Of the 29 patients with liver injury, 16 were ICs, but the remaining 13 were not (Figure 1a). (a) Patient selection criteria used in this study. (b) Dynamic monitoring of liver functions: The dotted line in red represents the ALT (left panel) and AST level (right panel) of liver injury patients from ICs patients. The dash-triangle line in blue represents the ALT (left panel) and AST level (right panel) of no liver injury patients from IC patients. AST, aspartate aminotransferase; ICs, inactive HBV carriers. In this study, 86 (59 men and 27 women) patients with influenza A with a median age of 67 years (IQR: 43–77) were included. Of these patients, 38 were ICs and 48 were infected with only influenza A. Of the 38 ICs, 16 (42.1%) had liver injury with a median age of 58.9 years (IQR: 45–70.5). Of the 48 patients infected with influenza A alone, 13 (27.1%) developed liver injury with a median age of 66.5 years (IQR: 60–82). Biochemical markers were monitored during hospitalization. Thirteen patients infected with influenza A alone who developed liver injury had a median peak ALT concentration of 66.5 U/L (IQR: 60–82) and a median peak AST concentration of 56.5 U/L (IQR: 35–56). All 13 patients had higher than normal ALT concentrations. Seven patients had higher than normal AST concentrations, and one had >3-fold higher AST concentrations. The patients' median peak ALP concentration was 131.3 U/L (IQR: 93–184). Four of these patients had high ALP concentrations ranging from 120 to 300 U/L. The patients' median peak GGT concentration was 115.2 U/L (IQR: 33–178). In three of these patients, GGT concentrations ranged from 57 to 142.5 U/L, and five had GGT concentrations >142.5 U/L. The patients' median peak LDH concentration was 288.2 U/L (IQR: 194–298). Seven of these patients had high LDH concentrations (>243 U/L). In the 16 ICs who developed liver injury, the median peak ALT concentration was 85 U/L (IQR: 57–90.8). Twelve patients had higher than normal ALT concentrations (1–3 fold), and four patients had even higher than normal ALT concentrations (>3 fold). The patients' peak median AST concentration was 71 U/L (IQR: 42.3–81.3). Nine patients had higher than normal ALT concentrations (1–3 fold), and three patients had even higher than normal ALT concentrations (>3 fold). The patients' peak median ALP concentration was 90.4 U/L (IQR: 65–101.8). One patient had high ALP concentrations ranging from 120 to 300 U/L, and the others had normal ALP concentrations. The patients' median peak GGT concentration was 87.8 U/L (IQR: 44–119). Eight patients had GGT concentrations ranging from 57 to 142.5 U/L, and three patients had GGT concentrations >142.5 U/L. The patients' peak median LDH concentration was 351.6 U/L (IQR: 187–282). Six patients had LDH concentrations >243 U/L (Table 1). Dynamic monitoring of liver function showed that ALT and AST concentrations were highest on the initial day of hospitalization and steadily decreased to normal concentrations after treatment in 17 ICs. However, AST concentrations continued to peak after 1–3 days of hospitalization in the seven control cases (Figure 1b). Previous studies have assessed the effect of respiratory viruses on liver injury in patients with underlying liver disease. Ciesek et al. [12] reported that patients with liver cirrhosis are at a high risk of a severe course of influenza, including organ failure, secondary infections, and death. This finding indicated that respiratory viruses are potential triggers of acute on chronic liver failure. Premkumar et al. [13] also reported that A/H1N1/09 influenza was associated with high mortality in liver cirrhosis. However, few studies have focused on the long-term follow-up of ICs [14]. Although ICs have a substantially higher risk of hepatocellular carcinoma and liver disease-related death than individuals who are not infected with HBV [15, 16], the effect of a respiratory virus (e.g., influenza A) on the liver function of people without pre-existing liver disease or of ICs is unknown. In our study, we found that influenza A infection led to liver injury in 27.1% of patients without pre-existing liver disease. However, influenza A infection led to a higher incidence (42.1%) of liver injury in ICs. The ICs experienced earlier onset and greater severity of liver injury than individuals who were affected only by influenza A, which indicated that ICs with influenza A infection predisposed them to liver injury. Our study showed that there was a high rate of liver injury after influenza A infection in patients who were ICs. A limitation of this study is that liver injury in ICs can occur before hospitalization. Further studies should be conducted with larger cohorts of ICs infected with influenza A. The influenza A infection leads to a higher incidence of liver injury in ICs than in patients infected with influenza A alone. Moreover, ICs experience earlier onset and greater severity of liver injury than individuals with only influenza A. Conceived and designed the experiments: Liqin Sun and Nan Xiao. Drafted and revised the manuscript: Hongzhou Lu, Xiao-Guang Li, and Jun Wang. Data collection: Yong-Mei Yin. Data analysis and interpretation: Jun Wang and Cheng Wang. Contributed analysis tools: Yong-Mei Yin. We are grateful to the doctors, nurses, disease control workers, and researchers for their assistance in treating influenza A under extreme conditions. Professor Hongzhou Lu is a member of the iLABMED Editorial Board. To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication. The remaining authors declare no conflicts of interest. Because it was a retrospective review of the Patient's registry and medical records, ethics statement was not applicable. Because it was a retrospective review of the Patient's registry and medical records, informed consent was not applicable. The data that support the findings of this study are available from the corresponding author upon reasonable request.
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关键词
influenza,liver abnormalities,infection,virus
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