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Effect of SARS-CoV-2 infection on liver function in patients with hepatitis B

BMC Infectious Diseases volume 24, Article number: 1428 (2024) Cite this article

Abstract

Objective

To investigate the impact of SARS-CoV-2 infection on liver function and prognosis in patients with HBV infection.

Methods

A total of 154 HBV-positive patients (HBV ( +) group) and 154 HBV-negative patients (HBV (-) group) diagnosed with COVID-19 at Taizhou Hospital between December 10, 2022, and January 31, 2023, were included in this study. Clinical characteristics, treatment, and laboratory findings were collected from patients at three time points: before (T1), during (T2), and at the time of discharge (T3) from SARS-CoV-2 infection.

Results

Compared to the HBV (-) group, the HBV ( +) group had a longer hospital stay (15 (9–22) days vs. 9 (5–16) days). Longitudinal comparisons of laboratory indicators from T1 to T3 showed a continuous decline in TP and ALB levels and a continuous increase in PT and TT levels in the HBV ( +) group. BUN levels increased during T2 and decreased thereafter. These differences were considered statistically significant (P < 0.05). Notably, the HBV ( +) group had a higher proportion of indicators elevated > 3 ULN from T1 to T2, including ALT (1.95%/5.19%), AST (3.25%/12.99%), ALP (1.95%/3.25%), GGT (4.55%/9.09%), TBIL (6.49%/9.09%), and DBIL (18.18%/22.73%). In the HBV (-) group, the elevations were mainly concentrated within 1–2 ULN, including AST (12.99%/22.08%), DBIL (10.39%/21.43%), BUN (12.99%/22.08%), CREA (20.13%/29.22%), and PLT (7.79%/14.94%). Furthermore, the incidence of liver injury from T1 to T3 was higher in the HBV ( +) group compared to the HBV (-) group (15.7% (20/127) vs. 7.2% (11/152), P < 0.05). Multivariate analysis showed that liver cirrhosis (HR = 4.847, 95% CI: 1.224–19.20, P = 0.025) and liver cancer (HR = 8.333, 95% CI: 2.156–32.209, P = 0.002) were independent risk factors for liver injury in the presence of SARS-CoV-2 infection.

Conclusion

SARS-CoV-2 infection has a higher proportion of liver injury in HBV-infected patients, affecting hepatic protein synthesis function. Those with cirrhosis and hepatocellular carcinoma are at higher risk of severe liver injury.

Peer Review reports

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant Omicron was first reported by the World Health Organization (WHO) in South Africa on November 24, 2021. Omicron infection was first confirmed in a sample collected on November 9, 2021 [1]. Owing to its highly mutated nature, the omicron variant can increase infectivity and immune evasion, posing a significant global health concern [2]. Besides primarily affecting the respiratory system, SARS-CoV-2 can cause multi-organ dysfunction, leading to complications such as acute cardiac injury, renal insufficiency, and liver damage [3,4,5]. While medical comorbidities such as hypertension, chronic lung disease, and heart disease have been identified as risk factors for adverse outcomes after SARS-CoV-2 infection [6], the influence of the Hepatitis B virus (HBV) on these outcomes remains unclear.

HBV infection is a significant public health issue with a global distribution, particularly in China [7]. Despite the decreasing incidence of new HBV infections due to vaccination, HBV remains the primary cause of liver cirrhosis and liver cancer, leading to numerous fatalities annually [8, 9]. Several recent studies have reported a relationship between COVID-19 and poorer liver function, liver damage, HBV reactivation, worse outcomes, and higher mortality rates in HBV patients [10,11,12,13,14,15]. However, the conclusions of these studies were inconsistent. These investigations were limited to small cohorts and lacked a comparison cohort without HBV infection. In addition, they lacked baseline data, particularly pre-admission information.

Further evidence is necessary to understand the association between COVID-19 and HBV infection. This study analyzed the baseline pre-admission data of 308 individuals with or without HBV infection to determine whether COVID-19 patients with HBV infection are more susceptible to severe illness by longitudinally examining their serologic markers and clinical characteristics.

Materials and methods

Study cohort

This retrospective study analyzed data from all hospitalized COVID-19 patients in three separate hospital districts of Taizhou Hospital between December 10, 2022, and January 30, 2023. Based on patients who were hepatitis C-negative, had no other liver disease, and had HBsAg or HBV DNA test results, we obtained a cohort of 154 patients in the HBV-positive COVID-19 group (HBV( +) group) and a matched cohort of 154 patients in the HBV-negative COVID-19 group (HBV(-) group) after applying the exclusion criteria and following the principles described above. We identified 154 individuals who tested negative for hepatitis C, had no other liver diseases, and were positive for HBsAg or HBV DNA to constitute the HBV-positive COVID-19 patient group (HBV( +) group). The control group, consisting of 154 HBV-negative COVID-19 patients (HBV(-) group), was carefully selected with exclusion criteria that included alcoholic liver disease, Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), cirrhosis, liver cysts, and liver cancer. The patient enrollment procedure is demonstrated in Fig. 1. This study was approved by the ethics committee of Taizhou Hospital of Zhejiang Province.

Fig. 1
figure 1

Study design and workflow. Abbreviations: COVID-19, coronavirus disease 2019; HbsAg, hepatitis B surface antigen; HBV, hepatitis B virus; MASLD,Metabolic Dysfunction-Associated Steatotic Liver Disease

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Clinical indicator analyses

We analyzed clinical indicators, including liver (ALT, AST, GGT, ALP, TB, DB, TP, and ALB), renal function (BUN and CREA), hepatitis B markers (HBsAg, HBsAb, HBeAg, HBeAb, HBcAg, and HBcAb), HBV DNA and coagulation function (PT, INR, APTT, FIB, TT, and PLT). Liver indices were measured using a Beckman Automatic Biochemical Analyzer (AU5821; Beckman Coulter, Brea, CA, USA). Coagulation function was assessed using an automatic coagulation analyzer (R Max, Stago, France), and HBV DNA amplification was conducted utilizing a state-of-the-art, fully automated thermocycler (7300 PLUS, ABI, USA). and hepatitis B markers were detected using an automatic immune analyzer (I2000, Abbott, USA). Quality control was conducted at two levels daily for all procedures, and all participated in the interlaboratory quality evaluation activities of the National Health Commission with excellent results.

Adult reference range: ALT: male: 9–50 (U/L), female: 7–40 (U/L); AST: male: 15–40 (U/L), female: 13–35 (U/L); ALP: male: 45–125 (U/L), female: 35–135 (U/L); GGT:male: 10–60 (U/L), female: 7–45 (U/L); TB: 3.4–20.5 (μmol/L); DB: ≤ 4.0 (μmol/L); TP: 65–85 (g/L); ALB: 35.0–55.0 (g/L); BUN: male: 3.60–9.50 (mmol/L), female: 3.10–8.80 (mmol/L); CREA: male: 57–111 (μmol/L), female: 41–81 (μmol/L); PLT: 125–350 (× 1012/L); PT: 11.0–14.5 (s); APTT: 28.0–42.0 (s); FIB: 2.0–4.0 (g/L); TT: 14.0–21.0 (s); Log10 HBV DNA: < 1.30 IU/ml.

Data collection and definition

Baseline data, clinical outcomes, hospital treatment, and laboratory test data were obtained from the Electronic Medical Record system and the Taizhou Health platform. Three time points were analyzed to conduct a longitudinal analysis of clinical indicators: the first time point, referred to as T1, corresponds to the pre-SARS-CoV-2 infection and is defined as six months prior to SARS-CoV-2 infection. The second time point, T2, represents the admission phase and includes the three-day period before and after SARS-CoV-2 infection. The third time point, T3, denotes the discharge phase and spans a three-day window before or after discharge. Liver injury was defined as elevated levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) exceeding three times the upper limit of normal (ULN), along with total bilirubin (TBIL) levels surpassing twice the ULN [16]. Acute-on-chronic liver failure (ACLF) was defined as TBIL levels exceeding 5 mg/dL (85 mmol/L), coupled with coagulopathy, defined as an international normalized ratio (INR) of 1.5 or prothrombin activity below 40%, occurring within four weeks, alongside clinical manifestations such as ascites and/or encephalopathy in patients with previously diagnosed or undiagnosed chronic liver disease/cirrhosis, following the guidelines established by the Asian Pacific Association for the Study of the Liver [17]. HBV stages were categorized by reporting clinicians through B-ultrasound or CT scans and classified as hepatitis B carriers, chronic hepatitis, cirrhosis and liver cancer. The grading criteria for SARS-CoV-2 infection are: Mild Type: Mild clinical symptoms without pneumonia in imaging; Moderate Type: Fever, respiratory tract and other symptoms with pneumonia in imaging; Severe Type: Respiratory distress, respiratory rate ≥ 30 times/min; in resting state, oxygen saturation ≤ 93%; PaO2/FiO2 ≤ 300 mmHg; Critical Type: Respiratory failure requiring mechanical ventilation, shock, and other organ failure requiring ICU monitoring and treatment [18]. Chronic Kidney Disease (CKD) is defined as an abnormality of the kidneys that persists for at least three months and affects health [19].

Statistical methods

Continuous and categorical variables are expressed as medians (quartile intervals) and counts (percentages). The Mann–Whitney U test was used for comparing continuous variables between two groups, the Kruskal–Wallis’s test was used for multiple comparisons, and the χ2 and Fisher’s tests were used for categorical variables. Logistic regression analysis was employed to evaluate risk factors for liver injury. IBM SPSS Statistics for Windows, version 22.0, was used for all the statistical analyses. Origin 2019b and R were used to draw graphs. Variables with a P-value < 0.05 were considered statistically significant.

Results

Demographic and clinical characteristics of COVID-19 patients with and without HBV

A total of 308 COVID-19 patients with and without HBV co-infection (154 vs. 154) were analyzed after matching. There were no significant differences in sex or age between the two groups. The median age and BMI were 61.5 vs. 64.6 and 23.7 vs. 22.3, respectively. Compared with COVID-19 patients without HBV exposure, those with HBV were more likely to have anorexia symptoms (42.2% vs. 21.5%), and their length of stay hospital was longer (15(9–22) vs. 9(5–16)). We found that there were indeed 35 CKD patients in the HBV group and 34 in the HBV-negative group, with no statistically significant difference in the prevalence of CKD between the two groups. There was one HBcAb-negative case in the HBV( +) group, but this case had a Log10 HBV DNA level of 2.82 IU/mL, so it was included in the study. The most frequently used anti-HBV drug before admission was entecavir; however, the levels of tenofovir and entecavir were approximately the same after admission. Interestingly, patients with COVID-19 but without HBV had a higher frequency of antiviral drug use for SARS-CoV-2. We compared and analyzed the liver and kidney functions of patients in the HBV( +) group and the HBV(-) group before and after the use of SARS-CoV-2 antiviral drugs during hospitalization. The results showed that the differences in liver and kidney functions before and after treatment with SARS-CoV-2 antiviral drugs were not statistically significant (Table S1).There were no significant differences in outcomes between the two groups. A statistically significant difference in SARS-CoV-2 infection severity was observed between the HBV-positive and HBV-negative groups (P < 0.001) (Table 1).

Table 1 Basic Characteristics of COVID-19 Patients With and without HBV Coinfection
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Longitudinal changes of serological indexes in COVID-19 patients with and without HBV

The dynamic changes in serum indexes at three time points (T1, T2, T3) were studied for both the HBV( +) and HBV(-) groups ( refer to Table 2). We found no significant difference in the changes in enzymatic indices (ALT, AST, GGT, and ALP) which represent liver cell damage, between the two groups throughout the three phases. However, the levels of these indices in the HBV( +) group were higher than those in the HBV(-) group. A comparison of baseline data (T1) between the two groups revealed that most of the indicators in the HBV( +) group were higher than those in the HBV(-) group.

Table 2 Serological analysis of COVID-19 Patients with and without HBV Coinfection at different time points
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There were significant differences in serum indexes (TP, ALB, PT, TT) representing liver synthetic function in the HBV( +) group. Compared with the baseline T1 stage, these indexes increased during the onset period at T2 and did not recover by discharge at T3. In the HBV(-) group, the serum indices (TB and DB) representing liver metabolic function showed significant differences in three-phase comparisons.

Between the three time points, the serum indexes BUN and APTT showed significant differences in both groups. Blood urea nitrogen (BUN) levels increased at time point T2 in both the HBV-positive (HBV( +)) and HBV-negative (HBV(-)) groups, returning to baseline levels at T3. In contrast, activated partial thromboplastin time (APTT) values increased at T2 in the HBV( +) group and continued to rise at T3, while in the HBV(-) group, APTT increased at T2 but returned to baseline levels by T3 (Table 2).

Analysis of HBV DNA in 34 HBV patients at different time

Among the 154 HBV patients, 34 had complete HBV DNA results at T1, T2, and T3 time points, and HBsAg results at T2. We analyzed the changes in HBsAg, Log10 HBV DNA levels, COVID-19 severity, and the use of antiviral medications (before and after hospitalization), as well as patient outcomes. During hospitalization, there was an increase in the number of patients using Entecavir or Tenofovir compared to pre-hospitalization. Among the 8 deceased patients, 1 had moderate COVID-19, 4 had severe COVID-19, and 3 had critical COVID-19. Define T1 as the baseline, HBV reactivation occurred in one deceased patient and the Log10 HBV DNA was elevated in four deceased patients. Out of 11 cases that showed a decrease in Log10 HBV-DNA from T1 to T3, 9 were patients who regularly took anti-HBV medication or started medication after admission (Fig. 2).

Fig. 2
figure 2

Changes in Log10 HBV DNA levels in 34 SARS-CoV-2( +) HBV( +) patients and their relationship with COVID-19 severity and antiviral treatment. Note: Severity of COVID-19:1: Mild, 2: Moderate, 3: Severe, 4: Critical; Entecavir before admission, Tenofovir before admission, Entecavir after admission, Tenofovir after admission: Colourless: No medication use, Blue: Medication use; Outcomes: Colourless: Improvement, Orange: Death

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Abnormal proportion of COVID-19 Patients with and without HBV Coinfection at different time points

In the HBV( +) group, the proportion of patients with > 3 ULN abnormalities in multiple indices increased from T1 to T2, including ALT (1.95%/5.19%), AST (3.25%/12.99%), ALP (1.95%/3.25%), GGT (4.55%/9.09%), TBIL (6.49%/9.09%), and DBIL (18.18%/ 22.73%).The abnormal proportions of TP, ALB, and BUN were significantly increased at T2 and were significantly different from those at T1 and T2 (P < 0.05). The proportion of AST abnormalities at T3 decreased to the level at T1; however, the proportion of abnormalities at T3 was dominated by 2–3 UNL and > 3 UNL.

Elevations in the HBV(-) group were mainly concentrated in 1–2 ULN, AST (12.99%/22.08%), DBIL (10.39%/21.43%), BUN (12.99%/22.08%), CREA (20.13%/29.22%), and PLT (7.79%/14.94%).

The abnormal proportions of AST, DBIL, and CREA decreased to T1 levels at T3. The abnormal proportion of AST at T3 significantly increased (P < 0.05). There were no significant changes in TBIL, TP, or ALB levels ( Fig. 3).

Fig. 3
figure 3

The proportion of patients with abnormal values of liver biochemistries over time in COVID-19 patients with HBV versus those without HBV infection. Note: 1–2 ULN: results between more than 1 × and 2 × reference range, 2–3 ULN: results between more than 2 × and 3 × reference range, > 3 ULN: results more than 3 × reference range; P1: HBV( +) T1 VS T2 VS T3, P2: HBV(-) T1 VS T2 VS T3

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Changes in liver injury in both groups of patients

The proportion of patients with liver injury at T1, T2, and T3 of HBV( +) patients was 17.5% (27/154), 25.3% (39/154), and 20.8% (32/154), respectively. The proportion of HBV(-) patients with liver injury at T1, T2, and T3 was 1.2% (2/154), 3.9% (6/154), 4.5% (7/154) respectively. There was no significant change in the duration from T1 to T3 between the HBV( +) group and the HBV(-) group (P > 0.05). There was no significant difference between the groups (P > 0.05). The proportion of liver injury at T1, T2, and T3 in HBV( +) positive patients was significantly higher than that in HBV(-) patients (P < 0.05).

The proportion of patients who experienced liver injury during the periods T1 to T2 and T1 to T3 was 28.6% (44/154) and 30.5% (47/154) in HBV( +) group, respectively, compared to 5.1% (8/154) and 5.8% (9/154) in HBV(-) group.

The proportion of patients without liver injury at stage T1 who then experienced a liver injury at T3 in the HBV( +) group was 15.7% (20/127), whereas, in the HBV(-) group, it was 7.2% (11/152). This difference was statistically significant (P < 0.05) (Fig. 4).

Fig. 4
figure 4

Proportion of HBV( +) and HBV(-) patients with liver injury by time period. Abbreviations: T1: Corresponded to the period before admission and was defined as within six months preceding admission; T2: Represented the admission phase and encompassed a three-day window before or after admission; T3: Denoted the discharge phase and spanned a three-day window before or after discharge; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, total bilirubin; COVID-19, coronavirus disease 2019; HBV( +),Hepatitis B positive; HBV(-), Hepatitis B negative

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Analysis of different indices and risk factors for liver injury of COVID-19 patients

Among these 308 patients, 45 had liver injury at the T2 stage, including 39 patients with HBV and 6 patients without HBV. A total of 263 patients did not have liver injuries. The mean age of patients with and without liver injury was 59.2 years (10.0%) and 63.8 years (14.7%), respectively (P < 0.05). Patients with and without liver injury suffered from Cardiovascular disease 4 (8.9%) vs. 72 (27.4%) respectively (p < 0.05). In the liver injury group, 6(13.3%) were admitted to the ICU, while in the non-liver injury group, 35 (13.3%) were admitted to the ICU (P > 0.05). The proportion of patients with cirrhosis and liver cancer in the liver injury group was 13 (28.9%) and 19 (42.2%), respectively. The rates of cardiovascular disease and entecavir/tenofovir utilization in liver and non-liver injury patients were 4 (8.9%) vs. 2 (27.4%) and 27 (60.0%) vs. 64 (24.3%) respectively, which were statistically significantly different(P < 0.05). The proportion of deceased patients was significantly higher in the liver injury group than in the non-liver injury group (10 (22.2%) vs. 22 (8.4%)), (P < 0.05). Upon further examination of the mortality causes, it was revealed that within the liver injury group, 9 out of 10 deceased patients (90.0%) had underlying cirrhosis or hepatocellular carcinoma, while only 1 (10%) did not. In stark contrast, among the 22 patients in the no liver injury group who succumbed, a mere only 2 (9.1%) had cirrhosis or hepatocellular carcinoma, with the remaining 20 (90.9%) lacking these conditions. The disparity between these two cohorts was statistically significant (P < 0.001). Moreover, the severity of SARS-CoV-2 infection also presented a statistically significant difference between individuals with and without liver injury (P = 0.020). The differences in PLT, PT, APTT, and FIB levels between the liver and non-liver injury groups were statistically significant. In patients with liver damage, the distribution of COVID-19 severity scores was as follows: Mild (15 patients, 33.3%), Moderate (12 patients, 26.7%), Severe (9 patients, 20.0%), and Critical (9 patients, 20.0%). In contrast, for patients without liver damage, the distribution was: Mild (109 patients, 41.5%), Moderate (96 patients, 36.5%), Severe (40 patients, 15.2%), and Critical (18 patients, 6.8%). The difference in severity distribution between the two groups was statistically significant (P = 0.020) (Table 3). When comparing the peak Log10 HBV DNA levels detected at T1, T2, and T3 stages between HBV patients with and without liver injury, no statistically significant difference was observed (P = 0.062) (Fig. 5).

Table 3 Differential analysis of patients with and without liver injury
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Fig. 5
figure 5

Comparison of Log10 HBV DNA levels in patients with and without liver damage.Note: 1.3 IU/ml: Normal reference value. Abbreviations: HBV DNA, Hepatitis B Virus Deoxyribonucleic Acid

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Logistic regression analysis of risk factors in patients with liver injury

Univariate logistic regression analysis of liver injury caused by SARS-CoV-2 infection revealed significant associations.

The univariate analysis indicated that age, HBV infection, liver cirrhosis, liver cancer, Severity of SARS-CoV-2 infection, entecavir/tenofovir use, PLT, PT, APTT, and FIB were associated with liver injury (P < 0.05). Multifactorial analysis showed that liver cirrhosis (yes vs. no, HR 5.654 (95% CI: 1.327–24.100), P = 0.019), liver cancer (yes vs. no, HR 11.641 (95% CI: 2.652–51.094), P = 0.001), SARS-CoV-2 Critical (yes vs. no, HR 13.251 (95% CI: 2.850–61.610), P = 0.001) and FIB ( change 1 g/L, HR 0.622 (95% CI: 0.451–0.859), P = 0.004) were significant predictors of liver injury (Table 4).

Table 4 Logistic regression analysis of risk factors in patients with liver injury
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ACLF in patients with hepatitis B liver injury

Among the 39 patients with liver injury, 7 progressed to ACLF, comprising 2 with liver cancer, 4 with liver cirrhosis, and 1 with chronic hepatitis. This progression resulted in 3 deaths, which included 2 from liver cancer and 1 from liver cirrhosis. The liver function indices of these deceased patients were significantly elevated compared to those of other patients with ACLF at T2. The time from admission to death for these patients was 20, 26, and 19 days, respectively.

Discussion

Since the relaxation of COVID-19 prevention policies, there has been a sudden increase in breakthrough cases. This retrospective study examined 308 patients with and without HBV infection to investigate changes in hepatic serological markers at three time points: pre-admission, admission, and discharge. Our study revealed notable differences in the alterations of hepatic synthetic function markers among patients with hepatitis B infection, resulting in a higher incidence of liver injury. Furthermore, there is an urgent need to treat liver cirrhosis and cancer in HBV-infected individuals.

Our results also indicated that anorexia symptoms and the length of hospital stay in the HBV( +) group were different from those without HBV. HBV is a noncytopathic virus commonly acknowledged as a disease associated with immune dysregulation [20]. Previous research has suggested that the duration of clearance of the novel coronavirus is prolonged in patients with HBV infection, leading to a potential prolongation of hospitalization. Clinical manifestations in HBV( +) patients mainly include decreased appetite, nausea, and upper abdominal discomfort, resulting in a higher incidence of inadequate nutritional intake. In our cohort, the primary antiviral drug used against COVID-19 was Azvudine (FNC), an oral inhibitor of the SARS-CoV-2 RdRp, which is the primary drug approved for treating adult COVID-19 patients in China [21]. FNC inhibits SARS-CoV-2 replication and enhances immune function in COVID-19 patients. According to recent research, there is no significant difference in the impact on liver and kidney function between Azvudine and nirmatrelvir-ritonavir (Paxlovid) when treating hospitalized patients with SARS-CoV-2 infection [22]. However, the safety and efficacy of FNC require extensive post-approval monitoring. Similarly, the choice of anti-HBV therapy warrants careful consideration. In our study, entecavir was the most frequently used anti-HBV medication prior to hospital admission, and post-admission, the use of tenofovir and entecavir was found to be roughly equivalent. A total of 21 patients changed their medication after admission, including 5 patients with chronic hepatitis B (including 1 pregnant woman), 7 patients with cirrhosis, and 9 patients with liver cancer. Although studies have shown that long-term use of tenofovir may have stronger adverse effects on kidney function and bone tissue compared to entecavir [23], there is also research indicating that the use of tenofovir in pregnant women is safe and has no adverse effects on mother or child [24]. For patients with decompensated cirrhosis, the impact of tenofovir on kidney function is less than that of entecavir [25]. Furthermore, in patients with chronic hepatitis B, especially those who are HBeAg-positive, the risk of liver cancer is significantly reduced with the use of tenofovir compared to entecavir [26]. Tenofovir is more effective than entecavir in suppressing viral RNA and DNA, potentially reducing viral load to a certain threshold more quickly, thereby reducing local inflammation and the subsequent risk of malignant transformation [27]. Before hospitalization, most HBV( +) patients were receiving entecavir or tenofovir antiviral therapy. Both drugs are nucleoside analogs that strongly bind to the RNA-dependent RNA polymerase (RdRp) of SARS-CoV, effectively terminating RNA synthesis catalyzed by SARS-CoV-2 RdRp [28]. The HBV( +) group received less antiviral treatment against COVID-19 than the HBV(-) group, likely due to their ongoing antiviral therapy for HBV. A multicenter study in Spain discovered that SARS-CoV-2 had a lower impact on individuals with HBV infection who underwent tenofovir treatment [29]. Tocilizumab or extensive use of intravenous steroid therapy has been shown to reactivate HBV in SARS-CoV-2 coinfections, resulting in delayed recovery from viral hepatitis and COVID-19 [30, 31]. Therefore, the safety and effectiveness of antiviral drugs against COVID-19 in HBV( +) patients require caution.

Longitudinal data analysis revealed that SARS-CoV-2 infection in HBV( +) patients primarily affected liver synthetic function markers, including TP, ALB, PT, APTT, and TT. However, no significant differences were observed in enzyme markers representing hepatocyte and bile duct damage. The trends of changes in these markers were generally consistent between the two groups. However, for HBV( +) patients, the changes in ALT, AST, ALP, GGT, TBIL, and DBIL were primarily elevated by 2–3 times the UNL, while HBV(-) patients generally exceeded by 1–2 times the UNL. Therefore, the effect of SARS-CoV-2 infection on hepatic serological markers varied between the two groups. This provides additional information for studies that did not initially include baseline data on HBV and SARS-CoV-2 co-infection. While there were significant variations in total bilirubin and direct bilirubin levels during the three stages in HBV(-) patients, the levels and proportion of abnormalities exceeding reference limits were significantly lower compared to HBV( +) group. These differences suggest that the observed variations may be due to a transient elevation.

Our study revealed a significant difference in liver injury between patients with and without HBV infection. Previous studies have indicated that SARS-CoV-2 infection can elevate liver function indicators and worsen liver damage in individuals affected by HBV infection. However, consensus on the differences in liver injury between COVID-19 patients with concurrent HBV infection and those without HBV infection is inconclusive. Studies by Liping Chen, Terry Cheuk-Fung Yip, Tian-Dan Xiang, and others suggest no significant difference in liver injury between HBV( +) and HBV(-) patients [12, 32, 33]. In contrast, Wu et al. reported a higher incidence of liver injury in HBV( +) patients [34]. Our findings reveal a higher occurrence of liver damage in the HBV( +) group when compared to the HBV(-) group. Out of individuals with no liver damage at T1, there were 127 HBV( +) patients and 152 HBV(-) patients. Later, in the subsequent stage (T2) after COVID-19 infection, 17 HBV( +) patients (11.1%) had a liver injury, whereas only six HBV(-) patients (3.9%) experienced such complications. Therefore, it can be inferred that SARS-CoV-2 has an impact on HBV( +) patients, with a more pronounced effect on liver injury in this population. In our study, the prevalence of cardiovascular comorbidities was lower in patients with liver injury than in patients without liver injury. Hypertension was present in 99 (64.3%) without liver injury with an age range of 63.8 ± 14.7 years. In comparison, there were 13 (28.9%) cases of hypertension in patients with liver injury with an age range of 59.2 ± 10 years. Hypertension is a recognised risk factor for cardiovascular disease [35]. And the prevalence of hypertension increases dramatically with age [36]. Numerous factors contribute to the development of liver injury. Through logistic regression analysis with single factors, HBV infection, and FIB have been identified as risk factors for liver injury. Notably, cirrhosis and liver cancer increased the likelihood of liver damage by 11.9 and 21.3 fold, respectively. Progressive liver damage and fibrosis caused by chronic HBV infection can lead to cirrhosis. Cirrhosis can further lead to liver cancer and coagulation dysfunctions. Thus, in the case of SARS-CoV-2 infection, the presence of cirrhosis and liver cancer intensifies the level of liver damage, which is consistent with the findings of our multifactorial analysis. Additionally, individuals with liver damage are more susceptible to severe illness, have worse prognoses, and have higher mortality rates. This situation is especially critical for individuals with underlying conditions such as cirrhosis and liver cancer. Research indicates a high short-term mortality rate related to HBV-associated acute-on-chronic liver failure (ACLF), with mortality ranging from 40 to 50% within 28 days [37]. In our study, we observed that 7 out of 39 patients with hepatitis B-related liver damage developed acute-on-chronic liver failure (ACLF), resulting in 3 fatalities. The time from admission to death for these patients was 20, 26, and 19 days, respectively. These findings underscore the extremely poor prognosis of ACLF and the rapid progression of the disease. When delving into the etiology of ACLF, it is imperative to consider two distinct pathogens: SARS-CoV-2 and HBV. SARS-CoV-2 can cause direct cytotoxicity, contribute indirectly to the inflammatory cytokine storm, hypoxic changes due to respiratory failure, endotheliitis, and drug-induced liver injury [38]. HBV is the primary cause of ACLF in our country [39]. These two mechanisms can both lead to acute deterioration of liver function, yet their pathophysiological characteristics and therapeutic responses may differ. Consequently, our study emphasizes that both HBV and SARS-CoV-2 infections could be triggers for ACLF, and co-infection with these two pathogens may exacerbate the severity of ACLF. Upon hospital admission, patients with liver cirrhosis and cancer exhibit abnormal liver function and coagulation dysfunction, emphasizing the significance of prompt intervention and treatment to prevent unfavorable outcomes. Studies have suggested that COVID-19 patients frequently manifest liver function and coagulation abnormalities. This may be attributed to the theory of microvascular thrombosis, supported by autopsy findings and observations of widespread portal vein and sinusoidal thrombosis [40]. Therefore, the risk of ACLF is high in patients with liver cancer and cirrhosis. Patients with HBV infection need to monitor their liver and coagulation functions upon hospital admission.

This was a retrospective study, and therefore, had some limitations. First, the sample size of the study population was relatively small, and there were some missing data, which could have affected the statistical power. Second, the study population was from a relatively homogeneous geographical region; therefore, the possibility of regional differences cannot be ruled out. Third, this study did not conduct a comparative analysis with non-COVID-19 patients with concurrent HBV infection. Fourth, the design of this study ignored patients who received treatment on an outpatient basis and patients with asymptomatic liver injury who did not seek medical attention. Future research with larger sample sizes and multicenter cohorts is necessary to better understand the impact of COVID-19 and HBV co-infection. Such studies would be beneficial for addressing these limitations and providing substantial evidence regarding the relationship between co-infection.

Conclusions

Our study shows that SARS-CoV-2 infection increases the incidence of liver injury and has a significant impact on hepatic protein synthesis in patients with hepatitis B virus (HBV). In particular, patients with cirrhosis and hepatocellular carcinoma are at higher risk of developing severe liver injury.

Data availability

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Sanyaolu A, Marinkovic A, Prakash S, et al. SARS-CoV-2 Omicron variant (B.1.1.529): A concern with immune escape. World J Virol. 2022;11(3):137–43.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Tian D, Sun Y, Xu H, et al. The emergence and epidemic characteristics of the highly mutated SARS-CoV-2 Omicron variant. J Med Virol. 2022;94(6):2376–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet (London, England). 2020;395(10223):507–13.

    Article  CAS  PubMed  Google Scholar 

  4. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–20.

    Article  CAS  PubMed  Google Scholar 

  5. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shi Y, Zheng M. Hepatitis B virus persistence and reactivation. BMJ. 2020;370:m2200.

    Article  PubMed  Google Scholar 

  8. Cooke GS, Andrieux-Meyer I, Applegate TL, et al. Accelerating the elimination of viral hepatitis: a lancet gastroenterology & hepatology commission. Lancet Gastroenterol Hepatol. 2019;4(2):135–84.

    Article  PubMed  Google Scholar 

  9. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736–1788.

  10. Zou X, Fang M, Li S, et al. Characteristics of liver function in patients with SARS-CoV-2 and chronic HBV coinfection. Clin Gastroenterol Hepatol. 2021;19(3):597–603.

    Article  CAS  PubMed  Google Scholar 

  11. He YF, Jiang ZG, Wu N, et al. Correlation between COVID-19 and hepatitis B: a systematic review. World J Gastroenterol. 2022;28(46):6599–618.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Xiang TD, Zheng X. Interaction between hepatitis B virus and SARS-CoV-2 infections. World J Gastroenterol. 2021;27(9):782–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu R, Zhao L, Cheng X, et al. Clinical characteristics of COVID-19 patients with hepatitis B virus infection - a retrospective study. Liver Int. 2021;41(4):720–30.

    Article  PubMed  Google Scholar 

  14. Sagnelli C, Montella L, Grimaldi P, et al. COVID-19 as Another Trigger for HBV Reactivation: Clinical Case and Review of Literature. Pathogens (Basel, Switzerland) 2022;11(7).

  15. Liu J, Wang T, Cai Q, et al. Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic hepatitis B virus infection. Hepatol Res. 2020;50(11):1211–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. China Digestion Association, Chinese Medical Doctor Association, Chinese Society of Hepatology, Chinese Medical Association. The protocol for prevention, diagnosis and treatment of liver injury in coronavirus disease 2019. LIN CHUANG GAN DAN BING ZA ZHI 2020; 36:1–4.

  17. Sarin SK, Choudhury A, Sharma MK, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update. Hep Intl. 2019;13(4):353–90.

    Article  Google Scholar 

  18. Diagnosis and treatment protocol for COVID-19 patients (Tentative 10th Version). Health Care Sci 2023;2(1):10–24.

  19. KDIGO 2024. Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2024;105(4s):S117-s314.

  20. Chen Y, Tian Z. HBV-Induced Immune Imbalance in the Development of HCC. Front Immunol. 2019;10:2048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang L, Wang Z. Bench-to-bedside: innovation of small molecule anti-SARS-CoV-2 drugs in China. Eur J Med Chem. 2023;257:115503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Su P, Yang CX, Wang XG. Azvudine versus paxlovid for oral treatment of COVID-19 in Chinese patients. BMC Infect Dis. 2024;24(1):44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu Z, Zhao Z, Ma X, et al. Renal and bone side effects of long-term use of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide fumarate in patients with Hepatitis B: a network meta-analysis. BMC Gastroenterol. 2023;23(1):384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pan CQ, Zhu L, Yu AS, et al. Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate for Preventing Vertical Transmission in Chronic Hepatitis B Mothers: A Systematic Review and Meta-Analysis. Clin Infect Dis. 2024;79(4):953–64.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yang X, Yan H, Zhang X, et al. Comparison of renal safety and bone mineral density of tenofovir and entecavir in patients with chronic hepatitis B: a systematic review and meta-analysis. Int J Infect Dis. 2022;124:133–42.

    Article  CAS  PubMed  Google Scholar 

  26. Choi WM, Yip TC, Wong GL, et al. Hepatocellular carcinoma risk in patients with chronic hepatitis B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis. J Hepatol. 2023;78(3):534–42.

    Article  CAS  PubMed  Google Scholar 

  27. Hur MH, Lee DH, Lee JH, et al. Extrahepatic malignancies and antiviral drugs for chronic hepatitis B: A nationwide cohort study. Clin Mol Hepatol. 2024;30(3):500–14.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jockusch S, Tao C, Li X, et al. A library of nucleotide analogues terminate RNA synthesis catalyzed by polymerases of coronaviruses that cause SARS and COVID-19. Antiviral Res. 2020;180:104857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lens S, Miquel M, Mateos-Muñoz B, et al. SARS-CoV-2 in patients on antiviral HBV and HCV therapy in Spain. J Hepatol. 2020;73(5):1262–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sanyaolu A, Marinkovic A, Abbasi AF, et al. Effect of SARS-CoV-2 infection on the liver. World J Virol. 2023;12(2):109–21.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Signorello A, Lenci I, Milana M, et al. COVID-19 in normal, diseased and transplanted liver. World J Gastroenterol. 2021;27(20):2576–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen L, Huang S, Yang J, et al. Clinical characteristics in patients with SARS-CoV-2/HBV co-infection. J Viral Hepatitis. 2020;27(12):1504–7.

    Article  CAS  Google Scholar 

  33. Yip TC, Wong VW, Lui GC, et al. Current and past infections of HBV do not increase mortality in patients with COVID-19. Hepatology. 2021;74(4):1750–65.

    Article  CAS  PubMed  Google Scholar 

  34. Wu J, Yu J, Shi X, et al. Epidemiological and clinical characteristics of 70 cases of coronavirus disease and concomitant hepatitis B virus infection: A multicentre descriptive study. J Viral Hepatitis. 2021;28(1):80–8.

    Article  CAS  Google Scholar 

  35. Fuchs FD, Whelton PK. High blood pressure and cardiovascular disease. Hypertension. 2020;75(2):285–92.

    Article  CAS  PubMed  Google Scholar 

  36. Buford TW. Hypertension and aging. Ageing Res Rev. 2016;26:96–111.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Philips CA, Ahamed R, Abduljaleel JK, et al. Critical Updates on Chronic Hepatitis B Virus Infection in 2021. Cureus. 2021;13(10):e19152.

    PubMed  PubMed Central  Google Scholar 

  38. Cai Y, Ye LP, Song YQ, et al. Liver injury in COVID-19: Detection, pathogenesis, and treatment. World J Gastroenterol. 2021;27(22):3022–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liang J, Liu L, Cao Y, et al. Hepatitis B-related acute-on-chronic liver failure induced by hepatotropic viral insult is associated with worse prognosis than that induced by non-virus insult. BMC Infect Dis. 2021;21(1):1273.

    Article  PubMed  PubMed Central  Google Scholar 

  40. D’Ardes D, Boccatonda A, Cocco G, et al. Impaired coagulation, liver dysfunction and COVID-19: Discovering an intriguing relationship. World J Gastroenterol. 2022;28(11):1102–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all participants for their cooperation in this study.

Clinical trial number

Not applicable.

Funding

No funding was received.

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Author notes

  1. Tong Sun and Hongbo Chi contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou, Medical University, 150 Ximen Road, Linhai, Taizhou, 317000, Zhejiang Province, China

    Tong Sun, Hongbo Chi, Jing Wang, Yufen Zheng, Hongguo Zhu, Jingxian Zhao, Kai Zhou, Mengyuan Chen, Donglian Wang, Jiaqin Xu & Bo Shen

  2. Evidence-Based Medicine Center, Taizhou Hospital of Zhejiang Province Affiliated to WenzhouMedical University, 150 Ximen Road, Linhai, Taizhou, Zhejiang Province, China

    Tao-Hsin Tung

  3. Key Laboratory of System Medicine and Precision Diagnosis and Treatment of Taizhou, 150 Ximen Road, Linhai, Taizhou, Zhejiang Province, China

    Mengyuan Chen & Bo Shen

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Contributions

TS: Definition, Methodology, Software, Formal analysis, Investigation, Data Curation, Writing-Original Draft, Project administration; HC: Definition, Methodology, Resources, Writing-Original Draft, Data Curation, Visualization; JW: Definition, Methodology, Writing-Original Draft; YFZ: Definition, Methodology, Investigation; HGZ: Data Curation, Resources, Project administration; JXZ: Data Curation, Resources; KZ: Methodology, Data Curation; THT: Definition, Methodology, Supervision; MYC: Definition, Methodology, Investigation; DLW: Resources, Data Curation; JJX: Definition, Methodology, Investigation, Conceptualization, Supervision, Project administration; BS: Definition, Methodology, Investigation, Conceptualization, Supervision, Project administration.

Corresponding author

Correspondence to Bo Shen.

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This research was approved by the ethics committee of Taizhou Hospital of Zhejiang Province (k20230116) and conforms to the declaration of Helsinki. Due to the retrospective nature of our study, the Medical Ethics Committee of Taizhou Hospital in Zhejiang Province has waived informed consent, and the data have been anonymized and kept confidential.

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Sun, T., Chi, H., Wang, J. et al. Effect of SARS-CoV-2 infection on liver function in patients with hepatitis B. BMC Infect Dis 24, 1428 (2024). https://doi.org/10.1186/s12879-024-10324-0

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BMC Infectious Diseases

ISSN: 1471-2334

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