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Therapeutic effects of reduced glutathione on liver function, fibrosis, and HBV DNA clearance in chronic hepatitis B patients

BMC Gastroenterology volume 25, Article number: 68 (2025) Cite this article

Abstract

Objective

To evaluate the therapeutic impact of reduced glutathione combined with entecavir on liver function, fibrosis, and HBV-DNA clearance in chronic hepatitis B patients.

Methods

This was a randomized controlled trial. This study included 90 patients diagnosed with chronic hepatitis B, who were randomly divided into two groups (observation group and control group) using a random number table, with 45 patients in each group. The control group received standard entecavir treatment (0.5 mg/time, once a day, continuous treatment for 3 months), while the observation group received a combination therapy of reduced glutathione and the standard entecavir treatment. Liver function markers (ALT, TBIL, AST, ALB), fibrosis markers (HA, PC III, LN), and liver fibrosis grades were assessed pre-and post-treatment. HBV-DNA negative conversion rates were recorded at 4, 12, 24, and 48 weeks. The incidence of adverse reactions, including nausea, vomiting, headache, and mild gastric discomfort, was recorded and compared between the two groups during the treatment period.

Results

ALT decreased from 348.96 ± 31.47 U/L to 31.11 ± 9.78 U/L in the observation group and from 347.90 ± 31.40 U/L to 56.90 ± 16.32 U/L in the control group (P < 0.05). TBIL decreased from 61.78 ± 4.94 µmol/L to 18.82 ± 2.93 µmol/L in the observation group and from 61.32 ± 4.93 µmol/L to 26.70 ± 4.44 µmol/L in the control group (P < 0.05). ALB increased from 29.65 ± 0.94 g/L to 48.76 ± 4.85 g/L in the observation group and from 29.77 ± 0.90 g/L to 34.12 ± 0.84 g/L in the control group (P < 0.05). The observation group showed greater reductions in HA, PC III, and LN, and improved liver fibrosis grades (P < 0.05). HBV-DNA negative conversion rates in the observation group were 15.56%, 35.56%, 60.00%, and 68.89% at 4, 12, 24, and 48 weeks, respectively, compared to 2.22%, 6.67%, 17.78%, and 42.22% in the control group (P < 0.05). Adverse reaction rates were 8.89% in the observation group and 20.00% in the control group (P > 0.05).

Conclusion

Reduced glutathione combined with entecavir significantly improves liver function, reduces liver fibrosis, and enhances HBV-DNA clearance in chronic hepatitis B patients without increasing adverse reactions.

Peer Review reports

Chronic hepatitis B is an ordinary clinical infectious illness. After the hepatitis B virus invades the liver, it can replicate a large number of viruses, seriously affecting the immune function of the liver, and then causing patients with decreased liver function, liver fibrosis, and cirrhosis [1,2,3]. Chronic hepatitis B is a challenging condition to manage due to its prolonged course, high risk of relapse, and unsatisfactory clinical outcomes, which collectively pose significant threats to patients’ health and quality of life [4,5,6]. Antiviral treatment is the most important way to clinically treat patients with chronic hepatitis B. It can inhibit the massive replication of hepatitis B virus, improve the injury to liver cells triggered by the virus and the series of immune reactions, and protect the liver. It also delays the development of the illness and cuts down the hazard of complications [7,8,9].

Accurate assessment of liver function and fibrosis is crucial for evaluating chronic hepatitis B progression and therapeutic efficacy [10]. Key biochemical markers, such as alanine aminotransferase (ALT), total bilirubin (TBIL), aspartate aminotransferase (AST), and albumin (ALB), are widely used to reflect liver function. ALT and AST are indicators of hepatocyte injury, TBIL reflects bile metabolism and excretion, while ALB indicates the liver’s synthetic capacity [11]. In addition, markers of liver fibrosis, including hyaluronic acid (HA), type III collagen (PC III), and laminin (LN), provide insights into the extent of extracellular matrix remodeling and fibrosis [12, 13]. These markers collectively offer a comprehensive evaluation of liver health, making them essential for monitoring therapeutic outcomes in chronic hepatitis B.

It is currently recognized that anti-fibrotic drugs are only effective for patients with liver fibrosis stage 3 and below [14]. When the disease develops into cirrhosis, it is difficult to reverse the patient’s condition with conventional clinical treatments. Therefore, antiviral drugs are selected in the early stages of chronic hepatitis B. Treatment combined with antioxidant and anti-fibrotic drugs to intervene in patients can delay the disease process to a certain extent [14]. Reduced glutathione is an antioxidant that can improve the damage to the liver caused by various adverse factors by maintaining the normal metabolism of cells in the body, eliminating oxygen free radicals, and other biochemical metabolic reactions [15,16,17]. Based on this, this investigation to discuss the auxiliary therapeutic impact of reduced glutathione on chronic hepatitis B patients and its impact on liver function and liver fibrosis, to offer a reference for improving the clinical remedy effect and improving the prognosis of chronic hepatitis B patients.

Materials and methods

General information

90 patients with chronic hepatitis B diagnosed in Qinhuangdao Third Hospital from October 2021 to October 2023 were opted to be the study samples. Inclusion criteria: (1) all meet the diagnostic criteria for chronic hepatitis B; (2) have complete clinical data; (3) HBV-DNA ≥ 2000 IU/mL; (4) all are initial anti-infective treatment; (5) meet the requirements of Helsinki declaration”. Exclusion criteria: (1) Patients with abnormal coagulation function [limits: prothrombin time (PT) between 10–14 seconds, activated partial thromboplastin time (APTT) between 25–40 seconds, and fibrinogen (Fib) levels between 2.0–4.0 g/L] and immunodeficiency [either primary immunodeficiency (congenital or hereditary conditions leading to impaired immune responses) or secondary immunodeficiency (conditions acquired through HIV infection, chronic immunosuppressive therapy, or severe malnutrition)]; (2) Patients with major heart, liver, kidney, and other organ disorders, including co-infection with hepatitis C virus (HCV), hepatitis D virus (HDV), or other chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and autoimmune hepatitis; (3) Patients with malignant tumors; (4) Patients with confirmed resistance to entecavir or reduced glutathione, as evidenced by prior treatment failure, documented drug resistance mutations, or lack of clinical response to these drugs in past therapies; (5) Patients with significant alcohol consumption, defined as more than 20 g/day for women or 30 g/day for men, or a history of alcohol-related liver disease [18].

Methods

Patients were randomly assigned to either the observation group or the control group using a computer-generated random number table created using SPSS software (version 21.0). To ensure a balance between groups, block randomization with a block size of 4 was applied. Randomization was conducted by an independent researcher who was not involved in patient enrollment, treatment administration, or outcome evaluation, ensuring allocation concealment. The randomization sequence was kept in a sealed, opaque envelope, which was opened sequentially by the recruiting team upon patient enrollment. This study could not achieve full blinding due to the nature of the intervention—reduced glutathione requires intravenous administration, while the control group only received oral entecavir therapy. As a result, both the patients and the treating physicians were aware of the group assignments. However, the outcome assessors were blinded to group assignments to minimize detection bias during data collection and analysis. To ensure blinding integrity, assessors were instructed not to discuss treatment details with patients, and patients were advised not to disclose their treatment to assessors. Additionally, separate locations were used for treatment administration and data collection to minimize the risk of unblinding. Regular audits of blinding procedures were conducted to ensure compliance. The control group conveyed entecavir (National Drug Approval No. H20052237, produced by Sino-American Shanghai Bristol-Myers Squibb Pharmaceutical Co., Ltd. ), 0.5 mg/time, 1 day/time, for 3 consecutive months. The observation group conveyed reduced glutathione treatment upon the control group. 1.2 g reduced glutathione (National Drug Approval No. H20031265, Shanghai Fudan Fuhua Pharmaceutical Co., Ltd.) was mixed with 100 mL of normal saline for intravenous infusion, 1 day/ times, continuous treatment for 3 months.

Observation indicators

(1) Therapeutic effect: The treatment effect can be divided into three categories: significantly effective, effective, and ineffective. The significantly effective definition is the normalization of liver function markers, including ALT < 40 U/L, AST < 40 U/L, TBIL < 21 µmol/L, ALB ≥ 35 g/L, And complete clearance of HBV-DNA (HBV-DNA < 20 IU/mL) and at least one stage reduction in liver fibrosis grading were evaluated by transient elastography. The effective definition is partial improvement in liver function markers, with a decrease of at least 50% in ALT and AST compared to baseline, a decrease of at least 30% in TBIL, an increase of at least 10% in ALB, and partial clearance of HBV-DNA (a decrease of at least 50% in HBV-DNA compared to baseline), but no significant change in liver fibrosis grading. Invalid is defined as no significant improvement in liver function markers (changes that do not meet the above criteria), no clearance of HBV-DNA, or progression of liver fibrosis. The overall treatment efficiency is calculated as follows: Compare the whole effective percentage of therapy, and divide it into markedly effective, effective, and ineffective. The whole effective rate of treatment (%) = (markedly effective + effective)/total number of cases × 100%. (2) Liver function indicators: Serum ALT, TBIL, AST, and ALB levels were measured using the G92000 fully automatic biochemistry instrument (provided by Beijing Medmeikang Biotechnology Co., Ltd.) at baseline (before treatment) and after completing the 3-month treatment. (3) Liver fibrosis indicators were measured employing radioimmunoassay to assess blood levels of HA, PC III, and LN in both groups. (4) HBV-DNA negative conversion rate: Compare the HBV-DNA negative conversion rate of the observation group and the control group at 4w, 12w,24w, and 48w after treatment. (5) Grading of liver fibrosis: Liver fibrosis in this study was assessed using transient elastography (FibroScan), a widely recognized non-invasive method for evaluating liver stiffness, which correlates with the degree of fibrosis. Fibrosis grading was determined based on liver stiffness measurements (LSM) expressed in kilopascals (kPa) and classified according to established thresholds. Patients without liver fibrosis (LSM < 6.0 kPa) were considered grade F0; patients with significantly expanded fibrosis in the portal area, and fibrosis limited to perisinusoidal areas and lobules (LSM ≥ 6.0 and < 7.5 kPa) were considered grade F1; patients with fibrosis around the portal area and the formation of fibrous septa but the preservation of lobular structure (LSM ≥ 7.5 and < 10.5 kPa) were considered grade F2; patients with fibrous septa and lobular structural disorder but no cirrhosis (LSM ≥ 10.5 and < 13.0 kPa) were considered grade F3, and patients with cirrhosis (LSM ≥ 13.0 kPa) were graded F4 [19]. (6) Adverse reactions during the treatment period were systematically observed and recorded for both groups, including nausea, vomiting, headache, and mild gastric discomfort. The severity of adverse reactions was graded based on the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 [20], which is a widely recognized and standardized classification system used in clinical research. The grading system is defined as follows: mild (Grade 1), where symptoms were minimal and required no intervention; moderate (Grade 2), where symptoms required symptomatic treatment but did not necessitate discontinuation of therapy; severe (Grade 3), where symptoms significantly interfered with daily life or required treatment modification or discontinuation; and life-threatening (Grade 4), where symptoms posed a serious risk and required immediate intervention. Detailed records were maintained for the type, onset time, duration, and medical interventions for all adverse reactions.

Statistical methods

SPSS 21.0 was opted to handle the data. The count data was shown as [n (%)]. The contrast between the two groups was computed by the x2 test. The measurement data was shown as (‾x ± s ). The sample size was determined based on a power analysis to ensure adequate statistical power (1 - β = 0.80) for detecting clinically meaningful differences between the two groups. Multivariable logistic regression analysis was used to identify independent predictors of treatment outcomes, such as liver function (e.g., ALT normalization) and fibrosis improvement. Variables included in the models were selected based on clinical relevance (e.g., baseline ALT, TBIL, HA, PC III, LN as critical markers of liver function and fibrosis), univariate analysis results (P < 0.10), and potential confounding factors (e.g., age and sex). The treatment group (test vs. control) was a primary independent variable of interest to evaluate the specific effect of reduced glutathione. Multicollinearity among predictors was assessed using the variance inflation factor (VIF), and variables with VIF > 5 were excluded or transformed. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for all predictors. The comparison between the two groups was computed by t test. P < 0.05 refers to the discrepancy being statistically obvious.

Results

General data

In the light of the random number table way, 90 samples of chronic hepatitis B patients were separated into an observation group and a control group, with 45 samples per group. 29 males and 16 females were in the observation group, aged 40 to 51 years old, with an average age of (46.16 ± 2.65) years, and a disease duration of 2 to 9 years, with an average disease duration of (6.20 ± 1.90) years; As for the control group, there were 27 males and 18 females, aged 39 to 51 years old, with an average age of (45.98 ± 2.66) years, and a disease duration of 2 to 9 years, with an average disease duration of (6.36 ± 1.81) years.No statistically obvious discrepancy in general data like gender and age had been found of the 2 groups (P > 0.05). Table 1 is as follows.

Table 1 Contrast of general data between the two groups
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Therapeutic effect

Contrasted with the whole effective percentage of remedy of patients in the control group, which was 82.22% (37/45), the whole effective percentage of remedy of patients in the observation group was 95.56% (43/45), which was significantly increased (P < 0.05). Table 2; Fig. 1 are as following.

Fig. 1
figure 1

Three-dimensional pie chart of the distribution of therapeutic effects for patients of the 2 groups

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Table 2 Analysis of therapeutic impacts of two groups of patients [n (%)]
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Liver function indicators

Contrasted with those before the intervention, the standards of ALT, TBIL, and AST in the 2 groups of patients after the intervention were obviously reduced, and the levels of ALB were risen (P < 0.05); Contrasted with the control group after the intervention, the standards of ALT, TBIL, and AST in the observation group were obviously higher than before intervention. TBIL and AST standards were significantly reduced, and ALB standards were significantly increased (P < 0.05). Table 3; Fig. 2 are as follows.

Fig. 2
figure 2

Violin plot comparing liver function indicators of the 2 groups after therapy. Note: Figure A is a violin plot contrasting the ALT levels of the observation group and the control group; Picture B is a violin plot contrasting the TBIL levels of the observation group and the control group; Picture C is a violin plot contrasting the AST levels of the observation group and the control group; Figure D is a violin plot contrasting the ALB levels of patients of the 2 groups; ****P < 0.0001

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Fig. 3
figure 3

Violin plot comparing liver fibrosis indicators of the 2 groups after therapy a violin plot contrasting the HA levels of the observation group and the control group; Picture B is a violin plot contrasting the PC III levels of the observation group and the control group; Picture C is a violin plot comparing the LN levels of the both groups; ****P < 0.0001

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Table 3 Contrast of ALT, TBIL, AST, and ALB levels of patients ( ‾\(\overline {\rm{x}} \,{\rm{ \pm }}\,{\rm{s}}\) )
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Multivariate logistic regression analysis was conducted to identify independent factors associated with liver function improvement, focusing on ALT, TBIL, AST, and ALB levels. The variables included in the model were treatment group (observation vs. control), baseline liver function indices (ALT, TBIL, AST, ALB), and patient demographics (age and sex). The results indicated that the observation group (OR: 2.15, 95% CI: 1.45–3.18, P < 0.01) and baseline ALT levels (OR: 1.12, 95% CI: 1.03–1.25, P < 0.05) were independent predictors of ALT normalization after treatment. Similarly, baseline TBIL levels (OR: 0.85, 95% CI: 0.76–0.93, P < 0.01) were inversely associated with TBIL reduction. The analysis further revealed that the observation group showed a higher likelihood of ALB improvement compared to the control group (OR: 2.30, 95% CI: 1.60–3.30, P < 0.01), after adjusting for baseline ALB levels and demographic factors (Table 4).

Table 4 Multivariate logistic regression analysis for liver function improvement
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Indicators of liver fibrosis

Compared with the levels of HA, PC III, and LN before remedy, the levels of patients in both groups were reduced after therapy (P < 0.05); Contrasted with the standards of HA, PC III, and LN of patients in the control group after therapy, the levels of patients in the observation group were obvious reduction (P < 0.05). Table 5; Fig. 3 are as follows.

Table 5 Contrast of liver fibrosis indicators of patients ( ‾\(\overline {\rm{x}} \,{\rm{ \pm }}\,{\rm{s}}\) )
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Multivariate logistic regression analysis was performed to determine the independent factors associated with liver fibrosis improvement, focusing on fibrosis markers (HA, PC III, LN) and transient elastography grading. Variables included in the analysis were treatment group (observation vs. control), baseline fibrosis markers, and patient demographics (age and sex). The analysis revealed that the treatment group (OR: 2.45, 95% CI: 1.65–3.65, P < 0.01) was a significant independent predictor of improved liver stiffness. Higher baseline HA levels were inversely associated with fibrosis improvement (OR: 0.88, 95% CI: 0.78–0.97, P < 0.05). Age was also a significant factor (OR: 0.95, 95% CI: 0.89–1.01, P = 0.05) (Table 6).

Table 6 Multivariate logistic regression analysis for liver fibrosis improvement
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HBV-DNA negative conversion rate

Compared with the control group, the HBV-DNA negative conversion percentage of patients in the observation group increased obviously at 4 weeks, 12 weeks,24 weeks, and 48 weeks after the remedy (P < 0.05). Table 7 is as follows.

Table 7 Contrast of HBV-DNA negative conversion rates of patients after therapy [n (%)]
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Grading of liver fibrosis

Compared with the degree of liver fibrosis of patients before treatment, patients in both groups were significantly improved after treatment (P < 0.05); compared with the degree of liver fibrosis of patients in the control group after treatment, patients in the observation group were significantly improved (P < 0.05). See Table 8.

Table 8 Analysis of liver fibrosis grading in two groups of patients
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Adverse reactions

In the observation group, adverse reactions were observed in 4 cases (8.89%), including 1 case of mild nausea and vomiting (Grade 1), 1 case of mild headache (Grade 1), and 2 cases of mild gastric discomfort (Grade 1). All reactions were self-limiting and resolved without the need for treatment modification. In the control group, adverse reactions occurred in 9 cases (20.00%), including 4 cases of mild nausea and vomiting (Grade 1), 2 cases of mild headache (Grade 1), and 3 cases of mild gastric discomfort (Grade 1). No moderate (Grade 2) or severe (Grade 3 and above) adverse reactions were observed in either group. The total incidence of adverse reactions showed no statistically significant difference between the two groups (P > 0.05). Table 9 is as follows.

Table 9 Contrast of the incidence of adverse reactions of patients [n (%)]
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Discussion

At present, clinical remedy of patients with chronic hepatitis B is mainly on the foundation of regular antiviral treatment, which can improve the patients’ liver function to a certain extent, turn HBV-DNA negative, delay the process of liver fibrosis, and has a definite impact on ameliorating the patients’ quality of life and survival rate. important significance [21,22,23]. However, conventional antiviral therapy has limited effect on repairing damaged cells and liver fibrosis, and the mechanism of liver fibrosis has not been fully signified, which brings difficulties to the clinical remedy of patients with chronic hepatitis B [24, 25]. The main components of reduced glutathione are glutamic acid, cysteine and glycine, which play an antioxidant role and can participate in the cyclic metabolic process of triphosphate and sugar metabolism and play a vital role; In addition, it can also induce an increase in the metabolism of protein and fat, improve cellular energy metabolism to the greatest extent, and promote material circulation in the body [26,27,28]. GSH plays a crucial role in maintaining cellular redox balance by directly clearing reactive oxygen species (ROS) and alleviating oxidative stress in chronic hepatitis B liver cells. Oxidative stress can lead to liver cell damage, inflammation, and fibrosis progression, while GSH can alleviate these effects by supplementing intracellular antioxidant reserves and stabilizing mitochondrial function [29, 30]. In addition, GSH has been shown to regulate immune response by downregulating pro-inflammatory cytokines such as TNF - α and IL-6 [31], which are typically elevated in chronic hepatitis B [32]. These anti-inflammatory effects may help limit liver inflammation and subsequent fibrosis. In addition, experimental studies have shown that the elevation of GSH can inhibit the activation of hepatic stellate cells [33], which is a key driving factor for extracellular matrix deposition and fibrosis, thereby preventing the progression of liver fibrosis [34].

This study analyzed the therapy effects and adverse reactions of the two groups and found that contrasted with the control group, the whole effective percentage of remedy was 82.22% (37/45), the whole effective percentage of the observation group was 95.56% (43/45), has a significant increase (P < 0.05), and the HBV-DNA negative conversion percentage of patients in the observation group 4w, 12w, 24w and 48w after remedy has an obvious increase (P < 0.05); There were 4 cases (8.89%) of adverse reactions in the observation group, including 1 case of mild nausea and vomiting (grade 1), 1 case of mild headache (grade 1), and 2 cases of mild gastric discomfort (grade 1). Based on time and clinical presentation, these adverse reactions may be related to the use of reduced glutathione, as intravenous antioxidant therapy typically reports nausea, vomiting, and stomach discomfort [35]. However, these symptoms are self limiting and can be resolved without adjusting treatment. There were 9 cases (20.00%) of adverse reactions in the control group, including 4 cases of mild nausea and vomiting (grade 1), 2 cases of mild headache (grade 1), and 3 cases of mild gastric discomfort (grade 1). These adverse reactions may be related to the use of entecavir, which has been reported to cause mild gastrointestinal symptoms and headaches in some patients [36]. Similarly, no moderate (grade 2) or severe (grade 3 or above) adverse reactions were observed in both groups, and the whole incidence of untoward effects in the observation group is 8.89% (4/45), no statistically obvious discrepancy had been found contrasted with the total incidence percentage of untoward effects in the control group of 20.00% (9/45) (P > 0.05). This shows that adjuvant treatment with reduced glutathione can significantly enhance the clinical efficacy of patients with chronic hepatitis B and increase the HBV-DNA negative conversion rate, and it can also maintain antiviral efficacy in the longer term without increasing excessive drug adverse reactions and has a certain degree of safety. The observed increase in HBV-DNA negative conversion rate in the observation group suggests that the combination therapy of reduced glutathione and entecavir may provide more sustained virological suppression. Reaching HBV-DNA negativity is an important milestone in the treatment of chronic hepatitis B, as it is associated with reduced viral replication and liver inflammation. Long term virological suppression has been shown to significantly reduce the risk of progression to cirrhosis, hepatocellular carcinoma (HCC), and liver related mortality [37, 38]. In addition, studies have shown that sustained HBV-DNA negativity is associated with improved liver function and regression of liver fibrosis, which is a key predictor of long-term survival in patients with chronic hepatitis B [39]. These findings emphasize the clinical significance of the observed increase in HBV-DNA negative conversion rate in this study, and highlight the potential of this combination therapy to improve long-term outcomes.

At present, the mechanism of liver fibrosis hasn’t been wholly signified. However, most studies indicate that the activation of hepatic stellate cells is an entry ticket to the process of liver fibrosis, resulting in the massive release of a variety of inflammatory factors, cytokines and oxidative stress responses. The occurrence of hepatic stellate cells can activate hepatic stellate cells and further induce their proliferation, synthesize a large amount of cell matrix, and deposit in the extracellular space, ultimately causing liver fibrosis [40, 41]. This study measured and evaluated the liver fibrosis indicators and grades of the two groups. It was found that compared with the postoperative control group, the levels of HA, PC III and LN in the observation group were significantly reduced, and the liver fibrosis grade was also improved. Significant improvement (P < 0.05). Further multivariate logistic regression analysis identified the treatment group as an independent predictor of liver fibrosis improvement, with an OR of 2.45 (95% CI: 1.65–3.65, P < 0.01). Baseline HA levels were inversely associated with fibrosis improvement (OR: 0.88, 95% CI: 0.78–0.97, P < 0.05), indicating that patients with lower baseline HA levels were more likely to achieve significant fibrosis improvement. Age was also found to be a borderline significant factor (OR: 0.95, 95% CI: 0.89–1.01, P = 0.05), with younger patients tending to show greater improvement in fibrosis markers and grades. The symptoms of chronic hepatitis B patients aren’t obvious in the early time. However, as the illness progresses, the liver function damage gradually increases, the rate of liver cell necrosis increases, and the regeneration ability weakens. Without timely and effective intervention, the risk of cirrhosis and liver cancer may increase. Increase [42, 43]. This study measured the liver function indexes of the two groups, The ALT level in the observation group significantly decreased from 348.96 ± 31.47 U/L before treatment to 31.11 ± 9.78 U/L after treatment, and the AST level decreased from 143.35 ± 8.68 U/L to 33.13 ± 8.99 U/L. Similarly, TBIL levels decreased from 61.78 ± 4.94 µ mol/L to 18.82 ± 2.93 µ mol/L, while ALB levels increased from 29.65 ± 0.94 g/L to 48.76 ± 4.85 g/L. In contrast, the control group also showed some improvement, but the degree of improvement was relatively low: ALT decreased from 347.90 ± 31.40 U/L to 56.90 ± 16.32 U/L, AST decreased from 142.89 ± 8.87 U/L to 59.70 ± 18.64 U/L, TBIL decreased from 61.32 ± 4.93 µ mol/L to 26.70 ± 4.44 µ mol/L, and ALB decreased from 29.77 ± 0.90 g/L to 34.12 ± 0.84 g/L (P all < 0.05). Further multivariate logistic regression analysis revealed that the treatment group was an independent predictor of liver function improvement, with an OR of 2.15 (95% CI: 1.45–3.18, P < 0.01). Baseline ALT levels also showed a significant association (OR: 1.12, 95% CI: 1.03–1.25, P < 0.05), indicating that higher baseline levels were predictive of greater improvement. Similarly, ALB improvement was independently associated with the treatment group (OR: 2.30, 95% CI: 1.60–3.30, P < 0.01), even after adjusting for baseline levels and demographic factors. These improvements have clinical significance in both daily life and long-term outcomes. For example, normalization of ALT and AST levels can alleviate symptoms of liver dysfunction such as fatigue, abdominal discomfort, and jaundice, thereby improving patients’ quality of life and daily activity ability. A significant increase in ALB levels can reduce the risk of common complications such as edema and ascites in patients with advanced liver disease, and improve overall nutritional and immune status [44]. In the long run, the sustained improvement of liver function markers is closely related to a reduced risk of disease progression, including cirrhosis and HCC [45]. This highlights the potential of combination therapy not only to improve biochemical parameters, but also to have a positive impact on patient survival and long-term health.

Liver fibrosis is a key determinant of disease progression, and higher fibrosis stages are associated with an increased risk of liver related complications, including cirrhosis, HCC, and liver failure [45]. Research has shown that fibrosis regression, even at one stage, can significantly reduce these risks and improve survival outcomes [46]. In addition, the improvement of liver function markers such as ALT, AST, and ALB reflects the enhancement of liver synthesis and metabolic capacity, which directly contributes to improving overall health and reducing disease burden. These changes are also related to improvements in quality of life, as they can alleviate common symptoms such as fatigue, jaundice, and gastrointestinal discomfort in patients with advanced liver disease [44]. Therefore, the combination therapy of reduced glutathione and entecavir may have a positive impact on the prognosis of patients, prolong survival, and improve quality of life by enhancing liver function and promoting fibrosis resolution. The above research results show that reduced glutathione adjuvant therapy plays an important role in improving liver fibrosis and liver function in patients with chronic hepatitis B. This is because it can exert liver protection and antioxidant effects and is a biological peptide synthesized by the human body, which is corrected with the human body, related to antioxidant substances [47]. patients with chronic hepatitis B have oxidative stress in their bodies, and reduced glutathione has the effect of clearing oxygen free radicals and maintaining the balance of antioxidant enzyme activity. It can also reduce the massive release of inflammatory factors [48, 49]. Entecavir is highly drug-resistant, can effectively inhibit HBV progene, and has high antiviral activity. Therefore, reduced glutathione-assisted entecavir treatment can maximize the therapeutic effect of the drug and play a complementary role [50, 51].

Transient elastography was chosen for its non-invasive nature, ease of operation, and ability to provide reliable fibrosis assessments in chronic liver disease. While liver biopsy remains the gold standard for fibrosis evaluation, its invasiveness and associated risks make it less suitable for routine clinical application [52]. In contrast, TE allows for repeatable and real-time assessment of liver stiffness, which correlates strongly with fibrosis stages [53]. However, it should be noted that TE may have limitations in distinguishing between early fibrosis stages (F0-F1), which could influence the sensitivity of the method in some cases [54]. In addition, this study was conducted at a single center, which may limit the generalizability of the research results to a wider population with different demographic or clinical characteristics. Further studies combining TE with other diagnostic tools, such as serum fibrosis markers, could provide a more comprehensive evaluation of liver fibrosis progression and therapeutic responses. Future multicenter studies with longer follow-up periods are needed to validate these findings and better evaluate the long-term benefits and limitations of this treatment approach.

In summary, reduced glutathione adjuvant therapy plays an important role in improving the therapeutic effect of patients with chronic hepatitis B. It can effectively reduce the patient’s liver function indicators and liver fibrosis indicators, improve the degree of liver fibrosis, and does not significantly increase the risk of adverse reactions, improving the patient’s HBV-DNA negative conversion rate.

Data availability

The experimental data used to support the findings of this study are available from the corresponding author upon request.

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Funding

Funding Source: Evaluating the impact of interferon therapy on hepatitis B surface antigen conversion and exploring strategies to improve efficacy.

Grant Number: 202401A134.

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Authors and Affiliations

  1. School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063210, Hebei, China

    Qiyao Wei & Jing Zhao

  2. The Third Hospital of Qinhuangdao, Qinhuangdao, 066000, Hebei, China

    Qiyao Wei

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Qiyao Wei: Conceptualization, Writing - original draft, Formal analysis, Investigation, Methodology. Data curation. Jing Zhao: Data curation, Investigation, Methodology. All authors reviewed the manuscript.

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Correspondence to Jing Zhao.

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Wei, Q., Zhao, J. Therapeutic effects of reduced glutathione on liver function, fibrosis, and HBV DNA clearance in chronic hepatitis B patients. BMC Gastroenterol 25, 68 (2025). https://doi.org/10.1186/s12876-025-03600-z

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BMC Gastroenterology

ISSN: 1471-230X

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