Safety of high-dose dual therapy for Helicobacter pylori eradication in patients with varying degrees of metabolic associated fatty liver disease

Abstract

Objectives

To evaluate the safety and efficacy of high-dose dual therapy (HDDT) for Helicobacter pylori (H. pylori) eradication in patients with varying degrees of metabolic associated fatty liver disease (MAFLD)

Methods

A total of 91 patients diagnosed with MAFLD complicated by H. pylori infection at the Department of Gastroenterology, Beijing Jishuitan Hospital, Capital Medical University, from October 2024 to December 2025, were enrolled. Based on liver transient elastography (FibroTouch) results, patients were divided into mild (n = 40), moderate (n = 28), and severe (n = 23) fatty liver groups. All patients received a 14-day HDDT regimen (vonoprazan fumarate 20 mg/dose, twice daily; amoxicillin 1.0 g/dose, three times daily). The primary outcome measure was changes in liver function (ALT, AST, GGT, ALP) before treatment and at treatment completion; secondary outcome measures were H. pylori eradication rate and incidence of adverse reactions

Results

Baseline ALT levels increased with the severity of fatty liver (mild 29.95 ± 16.90 U/L, moderate 38.24 ± 22.75 U/L, severe 49.63 ± 19.90 U/L, p < 0.01). At treatment completion, ALT and AST levels showed an increasing trend in patients with mild and moderate fatty liver but a decreasing trend in patients with severe fatty liver; however, none of the differences were statistically significant (p > 0.05). A total of 2 cases (2.2%) experienced transient mild elevation of transaminases (<2 times the upper limit of normal), which resolved spontaneously after drug discontinuation, and no grade 2 or higher drug-induced liver injury occurred. The eradication rates (ITT) in the three groups were 92.50%, 89.29%, and 91.30%, respectively, with no statistically significant difference between groups (p > 0.05). The total incidence of adverse reactions was 23.08%, mainly mild gastrointestinal symptoms such as bloating and nausea, with no serious adverse events

Conclusions

HDDT demonstrates good hepatic safety and high eradication rates in patients with mild to severe MAFLD who have mildly elevated liver enzymes. It can be recommended as a treatment option for H. pylori eradication in this patient population, but monitoring of liver function changes is advised.

1. Introduction

Metabolic associated fatty liver disease (MAFLD) is currently the most prevalent chronic liver disease worldwide. According to a 2023 meta-analysis, MAFLD affects approximately 30% of the global adult population (Zobair et al., 2023). With the epidemic of obesity and metabolic syndrome, MAFLD has become an important etiology of liver cirrhosis and hepatocellular carcinoma (Chinese Society of Hepatology and Chinese Medical Association, 2024). Meanwhile, although the infection rate of Helicobacter pylori (H. pylori) is declining, data from 2024 indicate that 42.8% of the population remains infected with H. pylori (Lu et al., 2024). Eradication of H. pylori is a key measure for preventing gastric cancer and peptic ulcers (Helicobacter pylori Study Group et al., 2022; Javier, 2025). Previous studies have shown that H. pylori infection can interfere with insulin signaling pathways by elevating inflammatory factors, leading to decreased insulin sensitivity; activate hepatic NADPH oxidase, triggering lipid peroxidation; reduce the activity of antioxidant enzymes such as superoxide dismutase in the liver, accelerating hepatocyte injury and apoptosis, thereby promoting the development and progression of MAFLD (Chen et al., 2025; Liu et al., 2023; Reham et al., 2024; Eudith et al., 2024; Michael et al., 2020), and H. pylori eradication can improve hepatic steatosis and related metabolic parameters in MAFLD patients (Yu et al., 2022). However, MAFLD patients often have varying degrees of liver function impairment, making the safety of eradication regimens a clinical focus. In traditional bismuth quadruple therapy, drugs such as clarithromycin, metronidazole, and tetracycline carry certain hepatotoxic risks and may induce drug-induced liver injury (DILI) (Zhang et al., 2026; Jeffrey et al., 2019; Fréneaux et al., 1988), especially in patients with pre-existing liver disease. In recent years, high-dose dual therapy (HDDT), which combines high-dose amoxicillin with a potent acid suppressant, has gained attention for its favorable efficacy and safety profile (Zhou et al., 2022; Jia et al., 2024). This regimen avoids hepatotoxic drugs used in traditional regimens. Amoxicillin is primarily excreted renally, with only a small portion metabolized by the liver, theoretically having minimal impact on liver function. However, some studies suggest that high-dose amoxicillin may increase the burden on the liver, posing a risk of liver injury (Ilaria et al., 2025), particularly in patients with pre-existing liver disease. This study aims to evaluate the hepatic safety, eradication efficacy, and adverse reaction profile of HDDT in patients with varying degrees of MAFLD, providing evidence for selecting H. pylori eradication therapy for this special population.

2. Materials and methods

2.1. Study subjects

This prospective, single-center, observational study enrolled patients who visited the Department of Gastroenterology, Beijing Jishuitan Hospital, Capital Medical University, from October 2024 to December 2025. Inclusion criteria: (1) Age 18–75 years; (2) Imaging-confirmed fatty liver, excluding alcoholic liver disease (male alcohol consumption <30 g/day, female <20 g/day), viral hepatitis, drug-induced liver disease, autoimmune liver disease; (3) Confirmed current H. pylori infection by ¹³C/¹⁴C urea breath test or pathological biopsy; (4) Agreed to participate and cooperate with the study. Exclusion criteria: (1) Significantly abnormal liver function (ALT or AST > 3 times the upper limit of normal); (2) Decompensated cirrhosis (Child-Pugh class B or C); (3) Severe renal insufficiency; (4) Penicillin allergy; (5) Pregnancy or lactation; (6) Use of antibiotics, bismuth agents, or proton pump inhibitors (PPIs) within the previous 4 weeks; (7) Concurrent malignancy or severe cardiopulmonary insufficiency.

2.2. Detection methods

All enrolled patients underwent FibroTouch liver transient elastography before treatment (Chronic Disease Management Branch of China Medical Biotechnology Association et al., 2025). The severity of fatty liver was quantitatively assessed using the ultrasound attenuation parameter (UAP) (Professional Committee of Digestive System Diseases and Chinese Association of Integrated Traditional Chinese and Weste rn Medicine, 2025; Qu et al., 2021): Normal liver: UAP < 244 dB/m; Mild fatty liver: 244 dB/m ≤ UAP < 269 dB/m; Moderate fatty liver: 269 dB/m ≤ UAP < 296 dB/m; Severe fatty liver: UAP ≥ 296 dB/m.

2.3. Treatment regimen

All patients received a 14-day HDDT regimen: Vonoprazan fumarate (Takeda Pharmaceutical Company Limited, Tianjin, Batch No.: J20200011) 20 mg/dose, twice daily; Amoxicillin (Guangzhou Baiyunshan Pharmaceutical General Factory, Batch No.: JD2307009A) 1.0 g/dose, three times daily, both administered orally for 14 days.

2.4. Data collection and Study Flow Diagram

Liver function parameters included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP). Detection was performed using the GCANA substrate method. Reagents and matching calibrators were purchased from Beijing Leadman Biochemistry Co., Ltd., and testing was conducted using the Hitachi LABOSPECT 008AS (fully automated biochemical analysis system). A repeat ¹³C urea breath test was performed, with a negative result defined as successful eradication. The intention-to-treat (ITT) eradication rate (number of successfully eradicated patients divided by total randomized population) and per-protocol (PP) eradication rate (number of successfully eradicated patients divided by the number of patients who actually completed the regimen and had complete data) were calculated. Compliance is calculated as the percentage of the number of tablets actually taken by the patient in the number of tablets planned to be taken. Less than 80% compliance is considered poor compliance and is not included in PP analysis (Figure 1).

FIGURE 1.

Study Flow Diagram.

2.5. Statistical methods

Data were processed using SPSS 27.0 statistical software. The Shapiro-Wilk test was used to assess the normality of measurement data, and Levene’s test was used to assess homogeneity of variance. Measurement data that were normally distributed with homogeneous variance were expressed as mean ± standard deviation. Comparisons between two groups were performed using independent-sample t-tests and paired t-tests, and comparisons among three groups were performed using analysis of variance (ANOVA). Comparisons between two groups were performed using the two-sample rank sum test. Count data were expressed as number (percentage), and intergroup comparisons were performed using the χ² test. A P-value < 0.05 was considered statistically significant.

3. Results

3.1. Baseline information of participants

A total of 91 patients were enrolled in this study, including 60 males (65.9%) and 31 females (34.1%), with a mean age of 41.16 ± 12.71 years. The mild, moderate, and severe fatty liver groups comprised 40, 28, and 23 patients, respectively. There were no statistically significant differences in baseline characteristics such as age, sex, GGT, and ALP among the three groups (P > 0.05), indicating comparability. Baseline the Body Mass Index (BMI), proportion of abnormal liver function, and ALT and AST levels increased significantly with the severity of fatty liver (P < 0.01), consistent with the progressive characteristics of MAFLD. See Table 1 for details.

TABLE 1.

Comparison of baseline data among the three groups (x̄±s).

Item	Mild (n = 40)	Moderate (n = 28)	Severe (n = 23)	p-Value
Sex (male/female)	26/14	15/13	19/4	0.092
Age (years)	43.53 ± 13.28	39.71 ± 13.38	38.83 ± 10.46	0.286
BMI(kg/m2)	25.65 ± 2.53	26.87 ± 2.34	28.45 ± 2.52	<0.001
ALFPs (n/N,%)	17/40 (42.50%)	14/28 (50.00%)	19/23 (82.61%)	0.007
ALT (IU/L)	29.95 ± 16.90	38.24 ± 22.75	49.63 ± 19.90	0.001
AST (IU/L)	24.30 ± 8.48	26.00 ± 8.59	30.96 ± 9.41	0.017
GGT (IU/L)	32.10 ± 20.34	34.43 ± 19.58	43.26 ± 32.05	0.196
ALP (IU/L)	77.35 ± 20.80	75.17 ± 19.10	82.09 ± 22.64	0.518

BMI, body mass index; ALFPs, Proportions of Abnormal Liver Function before treatment; ALT, Alanine Aminotransferase (0–40 IU/L); AST, Aspartate Aminotransferase (0–35 IU/L); GGT, Gamma-Glutamyl Transferase (0–45 IU/L); ALP, Alkaline Phosphatase (0–125 IU/L).

3.2. Changes in liver function

3.2.1. Comparison of liver function parameters before and after treatment

There were no significant changes in ALT, AST, and GGT levels before and after treatment among the three groups (p > 0.05). In patients with mild and moderate fatty liver, liver enzymes showed an increasing trend after treatment, with one patient in the mild group and one in the moderate group experiencing an elevation of liver enzymes to more than twice the normal upper limit (97 IU/L, 124 IU/L). In patients with severe fatty liver, liver enzyme levels showed a decreasing trend. ALP levels increased after treatment in all three groups but did not exceed twice the upper limit of the normal reference range (Table 2).

TABLE 2.

Comparison of liver function parameters before and after treatment among the three groups (IU/L, x̄±s).

Item	Mild			Moderate			Severe
	Pre-Rx	Post-Rx	p-Value	Pre-Rx	Post-Rx	p-Value	Pre-Rx	Post-Rx	p-Value
ALT	29.95 ± 16.90	33.67 ± 22.21	0.209	38.24 ± 22.75	42.96 ± 39.50	0.553	49.63 ± 19.90	45.35 ± 16.49	0.100
AST	24.30 ± 8.48	25.56 ± 11.30	0.393	26.00 ± 8.59	30.86 ± 14.61	0.221	30.96 ± 9.41	28.96 ± 8.48	0.210
GGT	32.10 ± 20.34	33.98 ± 31.38	0.560	34.43 ± 19.58	32.62 ± 26.85	0.831	43.26 ± 32.05	37.70 ± 25.33	0.048
ALP	77.35 ± 20.80	81.45 ± 19.14	0.044	75.17 ± 19.10	80.46 ± 19.08	0.153	82.09 ± 22.64	87.52 ± 25.36	0.112

Pre-Rx, Pre-treatment; Post-Rx, Post-treatment; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, Gamma-Glutamyl Transferase; ALP, alkaline phosphatase.

3.2.2. Comparison of changes in liver function after treatment based on pre-treatment liver function status

Results showed that patients with abnormal liver function before treatment had a decreasing trend in liver enzymes after treatment, whereas patients with normal liver function before treatment had an increasing trend in liver enzymes after treatment. The differences in the magnitude of change in ALT and AST between the two groups were statistically significant (p < 0.05). See Table 3 for details.

TABLE 3.

Comparison of changes in liver enzyme levels after eradication therapy based on pre-treatment liver function status (IU/L, x̄±s).

Groups	ALT	AST	GGT	ALP
Normal Pre-Rx (n = 41)	8.95 ± 30.97	4.59 ± 10.75	2.51 ± 18.04	4.84 ± 15.75
Abnormal pre-Rx (n = 50)	−4.73 ± 21.75	−0.39 ± 10.83	−24.56 ± 150.53	4.12 ± 11.43
p-Value	0.015	0.034	0.262	0.808

Pre-Rx, Pre-treatment; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, Gamma-Glutamyl Transferase; ALP, alkaline phosphatase.

3.3. H. pylori eradication rate

The overall ITT eradication rate for H. pylori with this regimen was 91.21% (83/91), and the PP eradication rate was 93.26% (83/89). Two patients were excluded: one for non-adherence to medication and one for failing to return for follow-up on time. There were no statistically significant differences in eradication rates among the three groups (P > 0.05). See Table 4 for details.

TABLE 4.

Comparison of H. pylori eradication rates among the three groups (%,n/N).

Group	ITT	PP
Mild MAFLD	92.50% (37/40)	94.87% (37/39)
Moderate MAFLD	89.29% (25/28)	92.59% (25/27)
Severe MAFLD	91.30% (21/23)	91.30% (21/23)
p-Value	0.899	0.852

ITT, intention-to-treat; PP, per-protocol.

3.4. Adverse reactions

A total of 21 patients (23.08%) experienced adverse reactions to this treatment regimen, all of which were mild. No serious adverse events leading to drug discontinuation occurred. The most common adverse reactions were gastrointestinal symptoms such as bloating, nausea, and loose stools. Other adverse reactions included dizziness and joint pain. The incidence of adverse reactions in the three groups was 22.50% (9/40), 25.00% (7/28), and 21.74% (5/23), respectively, with no statistically significant difference (p = 0.956). One patient in the mild fatty liver group was discontinued due to non-adherence to medication; one patient in the moderate fatty liver group was excluded due to delayed follow-up. Except for the patient who discontinued, all other patients had medication adherence >80%, with no significant difference among the three groups.

4. Discussion

This study is the first to evaluate the safety of HDDT for H. pylori eradication in patients with varying degrees of MAFLD. The results demonstrate that the HDDT regimen exhibits good hepatic safety in MAFLD patients with mild, moderate, and even severe fatty infiltration, with no cases of severe drug-induced liver injury, while maintaining a high eradication rate (>89%). This suggests that the regimen can be considered an alternative for H. pylori eradication in MAFLD patients.

The safety of H. pylori eradication in MAFLD patients has always been a challenge in clinical practice. Drugs in traditional eradication regimens, such as clarithromycin, metronidazole, and tetracycline, can potentially induce liver injury (Zhang et al., 2026; Jeffrey et al., 2019; Fréneaux et al., 1988). Clarithromycin, a CYP3A4 inhibitor, can interfere with hepatic drug metabolism, and cases of acute hepatitis induced by it have been reported (Jeffrey et al., 2019). Tetracycline antibiotics may cause microvesicular steatosis, with a higher risk particularly in patients with pre-existing liver disease (Fréneaux et al., 1988). The HDDT used in this study avoids these drugs, reducing the risk of hepatotoxicity from the perspective of drug selection. The pharmacokinetic properties of amoxicillin are the basis for its liver safety. After oral absorption, approximately 90% of amoxicillin is excreted unchanged in the urine via glomerular filtration and tubular secretion, with only a very small amount metabolized by the liver or excreted in bile; therefore, the risk of liver function impairment is low. However, the HDDT uses a relatively large amount of amoxicillin, and some studies suggest it may also cause liver injury (Ilaria et al., 2025). The results of this study show that in MAFLD patients, liver function parameters do show a certain increasing trend after H. pylori eradication with HDDT, suggesting that this regimen may increase the burden on the liver, and changes in liver function should be actively monitored.

This study also found an interesting phenomenon:patients with normal liver function before treatment showed an increasing trend in liver enzymes after treatment, whereas patients with abnormal liver function before treatment showed a decreasing trend in ALT, AST, and GGT after treatment. A possible reason for this is that for MAFLD patients with abnormal liver function, the elevated liver enzymes may not necessarily indicate progression to metabolic associated steatohepatitis (Reham et al., 2024; Chronic Disease Management Branch of China Medical Biotechnology Association et al., 2025); they may often be due to factors such as late nights, fatigue, or overeating superimposed on MAFLD. When these patients undergo H. pylori eradication therapy, seeing their abnormal liver function parameters may make them pay more attention to the researchers’ advice, improve their dietary and lifestyle habits, thereby reducing the burden on the liver and inflammatory response. The phenomenon of decreasing liver enzymes after treatment in MAFLD patients with previously abnormal liver function may also be influenced by factors such as small sample size and regression to the mean. Further investigation with larger sample sizes and control of confounding factors is needed to clarify the cause. In the severe fatty liver group, the proportion of patients with abnormal liver function before treatment was as high as 82.61% (19/23); therefore, the overall liver enzyme levels in this group showed a decreasing trend at the end of treatment, offsetting the burden caused by the therapeutic drugs. This indicates that the liver injury induced by the HDDT regimen is mild, and the regimen can be used in MAFLD patients with mildly elevated liver enzymes. Furthermore, educating patients to improve their diet and lifestyle can help in the management of MAFLD.

This study found that the overall ITT eradication rate of HDDT in H. pylori-infected patients with concurrent MAFLD was 91.21%, which is relatively ideal and consistent with previous reports on HDDT (Zhou et al., 2022; Shen et al., 2022; Qian et al., 2023; Yan et al., 2024; Soichiro et al., 2023; William et al., 2024). Vonoprazan, by competitively binding to the K+ binding site on the H + -K + -ATPase of gastric parietal cells, continuously inhibits gastric acid secretion, significantly increases intragastric pH, and enhances the sensitivity of antibiotics within the stomach (Takahisa et al., 2023; Wang et al., 2023), thereby more effectively killing H. pylori (Takahisa and David, 2010). There was no significant difference in eradication rates among the three groups, suggesting that the severity of MAFLD does not affect the efficacy of this regimen. This may be because amoxicillin is a time-dependent antibiotic (Yang et al., 2025); its efficacy depends mainly on the duration that the drug concentration exceeds the minimum inhibitory concentration, rather than on hepatic metabolic function. High-dose, frequent administration ensures that an effective concentration of the drug is maintained in the gastric mucosa, overcoming the slight impact liver disease might have on drug distribution.

The total incidence of adverse reactions observed in this study was 23.08%, similar to previous reports (William et al., 2024) but lower than the incidence reported for bismuth quadruple therapy (Eudith et al., 2024; Zhang et al., 2026; Zhang et al., 2025). The adverse reactions in this study were mainly gastrointestinal symptoms such as bloating, nausea, and diarrhea, which may be related to gastric mucosal irritation and disruption of the gut microbiota caused by high-dose amoxicillin. However, they were mild and resolved quickly after drug discontinuation.

This study has some limitations. First, it was a single-center, non-randomized controlled study with a relatively small sample size. Factors that may affect MAFLD, such as blood glucose and blood lipids, were not monitored, which may affect statistical power. Second, the follow-up period was short, making it impossible to assess long-term liver function and the durability of eradication efficacy. Third, liver biopsy was not performed as the gold standard for MAFLD diagnosis and fibrosis staging, although transient elastography is a recognized non-invasive alternative. Future studies should further expand the sample size, conduct multicenter randomized controlled trials, include a broader spectrum of liver disease, focus on the impact of liver fibrosis, and extend the follow-up period to better evaluate the safety and efficacy of the HDDT regimen in MAFLD patients.

In conclusion, high-dose dual therapy demonstrates favorable hepatic safety and high eradication rates for H. pylori in patients with varying degrees of MAFLD. The regimen avoids some hepatotoxic drugs used in traditional eradication regimens and may be considered as a potential option for MAFLD patients with mildly elevated liver enzymes. However, it should be emphasized that, given the single-center, observational design with a small sample size, these findings require further validation in larger, multicenter randomized controlled trials. Monitoring of liver function during treatment is recommended.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by Beijing High-level Public Health Technical Talent Construction Project (Subject Backbone 02- 19).

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by Ethics Committee of Beijing Jishuitan Hospital, Capital Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

LZ: Data curation, Formal Analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing. HL: Data curation, Formal Analysis, Writing – original draft. LL: Funding acquisition, Methodology, Project administration, Writing – review and editing.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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