Liver fibrosis is a condition characterized by the accumulation of scar tissue (fibrous tissue) in the liver as a response to chronic liver injury or inflammation. This disease is a progressive process that can cause significant liver dysfunction, which can develop into cirrhosis and liver failure if not treated appropriately.[1]

The most common causes of liver fibrosis are chronic viral hepatitis infections (such as hepatitis B and hepatitis C), alcohol-related liver disease, MAFLD and Nonalcoholic Steatohepatitis (NASH), autoimmune liver disease (such as autoimmune hepatitis), liver disease with a genetic history (such as hemochromatosis and Wilson's disease), bile duct disease (such as primary biliary cholangitis and primary sclerosing cholangitis), and chronic exposure to toxins or certain medications.[2]

The study reported that the prevalence of liver fibrosis is estimated to be around 9.5% in general populations. Multivariate analysis indicates that liver fibrosis is associated with several risk factors, such as diabetes (OR=2.43, 95% CI=1.8 to 3.28), obesity (OR=1.77, 95% CI=1.35 to 2.32) (all p<0.001), metabolic syndrome (OR=1.4, 95% CI=1.05 to 1.87) (p=0.024), HBsAg positive (OR=3.49, 95% CI=2.55 to 4.79), and abnormal liver function tests (OR=1.9, 95% CI=1.49 to 2.42).[3]

A study by Hong et al. showed that patients with hepatitis B accompanied by MAFLD were more likely to experience significant fibrosis (35.5% vs. 23.5%, p <0.001) than those with hepatitis B alone. MAFLD significantly increases the risk of liver fibrosis in patients with hepatitis B (OR: 2.055, 95% CI 1.635–2.584; p < 0.001).[4]

Wang et al. studied the association between MAFLD and the risk of cirrhosis in patients with hepatitis B in 355 patients in China and found that MAFLD increased the risk of cirrhosis 1.7-fold [OR 1.790; p = 0.020], diabetes mellitus 1.8-fold (OR 1.883; P=0.041), non-antiviral treatment 2-fold (OR: 2.037; P=0.013), and initial serum HBV DNA levels 1.7-fold (>2.4 log10 IU/mL, OR :1.756; P=0.045).[5] The aim of this study was to determine the effect of hepatitis B and MAFLD on the incidence of liver fibrosis.

A descriptive study using a cross-sectional method. It involves all patients diagnosed with hepatitis B at Wahidin Sudirohusodo General Hospital in Makassar between August 2024 - February 2025. The study was conducted after receiving ethical clearance from the Biomedical Research Ethics Committee of the Faculty of Medicine, Hasanuddin University, Makassar, with no. 48/UN4.6.4.5.31 / PP36/ 2025.

The inclusion criteria for this study included patients diagnosed with hepatitis B based on hepatitis B antigen serum, aged > 18 years, and undergoing transient elastography (FibroScan) examination. The criteria for MALFD were based on the presence of hepatic steatosis accompanied by obesity, type 2 diabetes mellitus, or metabolic syndrome. The metabolic syndrome parameters included in this study are Body Mass Index (BMI), total cholesterol, and triglycerides.

The demographic and clinical data collected when patients first arrived at the hepatobiliary clinic included gender, age, BMI, total cholesterol, triglycerides, HBsAg, HBeAg, HBV DNA, and clinical examination data such as transient elastography. Based on the demographic data, patients were divided into two groups: patients with hepatitis B and patients with hepatitis B and MAFLD.

Data processing was performed using the statistical program SPSS version 25. Univariate data were described in the form of means (standard deviation/SD) or medians (range) for numerical data and in the form of proportions for categorical data. Multivariate analysis used logistic regression, reported as prevalence odds ratios (POR) with 95% confidence intervals (CI). P-values <0.05 were considered statistically significant.

This study involved 98 patients categorized into two groups: group 1 55 patients (56.1%) with hepatitis B, and group 2 43 patients (43.9%) with hepatitis B and MAFLD. In Group 1, 61.8% were male and 38.2% were female with an average age of 52.1 ± 13.7 years. In Group 2, 44.2% were male and 55.8% were female with a slightly lower average age, such as 50 ± 12.1 years. (Table 1)

Table 1. Study Characteristics

Based on the results of transient elastography, group 2 had significantly higher liver stiffness (p<0.05) compared to group 1 (11.19 kPa vs 17.1 kPa). (Table 2)

Table 2. Comparison of liver stiffness between group 1 and group 2

Figure 1. Comparison of liver stiffness between group 1 and group 2

Analysis of the association between hepatitis B and MAFLD with the severity of fibrosis showed that group 2 more frequently suffered advanced liver fibrosis than group 1 (60.6% vs. 39.4%). Patients in group 2 had a 2.8-fold risk of developing advanced liver fibrosis (OR: 2.809; 95% CI 1.184-6.664; p = 0.017). (Table 3)

Table 3. Association between hepatitis B and MAFLD with the severity of liver fibrosis

Multivariate analysis of factors associated with the incidence of liver fibrosis showed that HBeAg-negative was significantly associated with a higher incidence of liver fibrosis than HBeAg-positive (OR: 11.610; 3.766 - 35.791 95% CI; p < 0.05). (Table 4)

Table 4. Analysis of factors associated with the incident of liver fibrosis

This study found that hepatitis B patients with MAFLD had significant higher liver stiffness than patients with hepatitis B alone. In addition, a significant association was found between hepatitis B and MAFLD with the severity of liver fibrosis. Hepatitis B patients with MAFLD are more likely to experience advanced liver fibrosis than those with hepatitis B alone (60.6% vs. 39.4%) and are 2.8-fold more likely to have advanced liver fibrosis (OR: 2.809; 95% CI 1.184-6.664; p = 0.017).

A retrospective study by Choi et al. in 1,089 patients with chronic hepatitis B and MAFLD found that the co-occurrence of hepatitis B and MAFLD was associated with a higher rate of liver fibrosis compared to patients with hepatitis B alone (OR: 4.8, 95% CI: 2.6-9., p<0.001).[6] Similar results were also reported by Chan et al., where patients with hepatitis B accompanied by MAFLD had higher levels of liver fibrosis compared to those suffering from hepatitis B alone.[7]

Hepatitis B and MAFLD are two conditions that can contribute to the incidence of liver fibrosis. Recurrent episodes of liver injury due to viral hepatitis lead to the formation of fibrotic tissue in the liver. Hepatitis B virus infection can trigger an inflammatory process that leads to hepatocyte damage and stimulation of fibrosis through activation of hepatic stellate cells.[8] Meanwhile, MAFLD associated with metabolic syndrome such as obesity and insulin resistance, can also lead to liver fibrosis due to progressive fatty liver and chronic inflammation. Excessive accumulation of free fatty acids in the hepatocytes causes mitochondrial dysfunction leading to increased oxidative stress, production of toxic lipid metabolites and hepatocyte injury.[9]

The incidence of liver fibrosis in chronic hepatitis B patients previously mentioned by Machado, et al, where the incidence of liver fibrosis was associated with metabolic factors, such as high body mass index, diabetes, and hyperlipidemia. Metabolic factors have the most important association for liver fibrosis. Individuals with obesity and diabetes mellitus have a 2.5- to 6-7-fold increased risk of hepatic steatosis compared to normal individuals.[10] In addition, many studies have concluded that increased body mass index, dyslipidemia, hypertriglyceridemia and hypercholesterolemia show a positive association with the incidence of hepatic steatosis.

Hepatitis B e-antigen or HBeAg is a protein from the hepatitis B virus that circulates in infected blood when the virus is actively reproducing. Even if the HBeAg test is negative in someone previously diagnosed with hepatitis B, close monitoring must be carried out.

In this study, patients with negative HBeAg were found to be more common than positive HBeAg (60.2% vs 39.8%). Multivariate analysis found that HBeAg negative was significantly associated with the incidence of advanced liver fibrosis compared to HBeAg positive (OR: 11.610; 3.766 - 35.791 95% CI; p < 0.05).

A study by Chen, et al. reported that HBeAg negative patients had 2-fold risk of liver fibrosis compared to HBeAg positive in patients with hepatitis B who had MAFLD (OR: 2.02; 95% CI: 1.09 - 3.73; p < 0.026).[11] Similar results were also found by Wu et al who suggested that negative HBeAg is one of the risk factors of liver fibrosis in chronic hepatitis B patients.[12]

Both HBeAg-negative and HBeAg-positive hepatitis are two characteristic types of chronic hepatitis B with different clinical features. HBeAg-negative is characterized by poor spontaneous remission, sudden increase in ALT, easy progression to cirrhosis, and low HBV DNA titer, which makes it difficult to initiate therapy. These conditions allow for significant liver fibrosis in HBeAg-negative patients compared to HBeAg-positive patients.[13]

This study has several limitations such as a small sample size and focusing on one health center. Some parameters of MALFD were also not measured such as waist circumference, blood pressure, HbA1c levels and C reactive protein levels which might provide more optimal results. Nevertheless, the results obtained in this study still provide significant information that hepatitis B patients with HBeAg negative accompanied by MAFLD need close monitoring and more aggressive therapy to prevent liver fibrosis.

In this study, it can be concluded that patients with hepatitis B accompanied by MALFD have higher liver stiffness than patients with hepatitis B alone. HBeAg negative is the most influential factor for the incidence of liver fibrosis.

CONFLICT OF INTEREST

Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interests, patent/licensing arrangements, etc.) that might give rise to a conflict of interest with respect to the submitted article.

AUTHOR CONTRIBUTIONS

YSR (Concept, Design, Sources, Materials, Data Collection and Processing, Analysis and Interpretation, Literature Search, Manuscript Writing). FA (Concept, Design, Supervision, Analysis and Interpretation, Literature Search). HI (Concept, Design, Supervision, Analysis and Interpretation, Literature Search). SB (Concept, Design, Supervision, Analysis and Interpretation, Literature Search).  WU (Concept, Design, Supervision, Analysis and Interpretation, Literature Search). AS (Concept, Design, Analysis and Interpretation, Critical Review). All authors were involved in drafting the manuscript, revising it, and evaluating its content. They have all read and approved the manuscript, confirming the accuracy and integrity of the research details. All author read and approve the final manuscript.

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