ABSTRACT
Background and Objectives: Evaluation of liver fibrosis is imperative in the management of chronic hepatitis B. Metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH) with necroinflammation contribute significantly to liver damage. This study aims to investigate the role of vibration-controlled transient elastography (FibroScan®) as a non-invasive method for diagnosis and treatment follow-up. Methods: The study was prospectively planned in four different centers. Patients who were positive for hepatitis B surface antigen for more than 6 months and had an HBV-DNA > 2000 IU/mL underwent liver biopsy and FibroScan®. FibroScan® was performed before antiviral therapy and 1 year after treatment. Results: A total of 70 patients were included in the study. The mean age was 37.1 years, and 70.0% of the patients were male. The concordance rate with simultaneous elastography in 68 biopsies was 97.1% (P < 0.001). In 66 patients (97.0%), the liver fibrosis score was ≥ 2 or the hepatic activity index was ≥ 6. At the beginning of antiviral treatment, 19 patients (27.1%) had MASLD and 6 patients (8.6%) had MASH. The MASLD rate decreased to 25.7% (P = 0.064), and there was no change in MASH rate at the end of 1 year. The concordance rate with liver biopsy was found to be acceptable. Conclusion: FibroScan® was as useful as liver biopsy in the evaluation of chronic viral hepatitis-associated fibrosis as well as in the diagnosis and follow-up of concomitant MASLD/MASH.
Key words: chronic hepatitis B, metabolic syndrome, hepatic fibrosis, hepatic steatosis, metabolic-dysfunction associated steatotic liver disease/metabolic-dysfunction associated steatohepatitis, FibroScan®
INTRODUCTION
Chronic hepatitis B (CHB) is a significant global public health concern that affects millions of individuals. It increases the risk of severe complications such as liver cirrhosis and hepatocellular carcinoma (HCC).[1–3] There is currently no cure for CHB. Nucleos(t)ide antivirals suppress viral replication and reduce liver inflammation and fibrosis. However, fibrosis persists in a certain group of patients with or without therapy. Therefore, it is critical to monitor liver fibrosis to prevent the progression to advanced stages, which leads to severe liver damage.[2]
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly nonalcoholic fatty liver disease, is a clinicopathologic description of patients with little or no history of alcohol consumption who have histological features indicative of liver damage like that induced by alcohol. Features range from fat accumulation in hepatocytes (simple hepatic steatosis) to necroinflammatory (steatohepatitis). Fibrosis may also be seen and is called metabolic dysfunction-associated steatohepatitis (MASH), formerly nonalcoholic steatohepatitis. MASH progresses to cirrhosis in 20% of patients. MASH is now recognized as a leading cause of cryptogenic cirrhosis.[4,5]
It is generally accepted that hepatic steatosis causes or triggers fibrosis in patients with CHB.[6] Obesity, metabolic syndrome, MASLD, and MASH may also accompany comorbidities with CHB.[7–9] There is increasing evidence that hepatic steatosis and metabolic dysfunction increase the risk of progression to HCC in patients with CHB, and patients with chronic liver disease, including CHB, should be evaluated for MASLD.[10]
Liver biopsy is the gold standard to assess steatosis and fibrosis. It is used for both diagnosis evaluation and during treatment in patients with CHB.[2–11] While liver biopsy is a valuable diagnostic tool, it has several disadvantages, including subjectivity, risk of complications, fears and concerns of patients, and invasiveness. There is a significant need for simple, safe, and non-invasive methods of fibrosis evaluation.[12–13] FibroScan® is a non-invasive diagnostic tool and has been validated for the assessment of liver fibrosis in CHB patients. There is a significant correlation with histological fibrosis stages and high diagnostic accuracy.[2,14,15] However, biopsy is mandatory by insurance companies in some countries before starting treatment for CHB.
The aim of the study was to evaluate the consistency between liver biopsy and FibroScan® evaluation of liver stiffness measurement (LSM) for fibrosis and controlled attenuation parameter (CAP) for steatosis in patients with CHB. The secondary aim of the study was to demonstrate the efficacy of FibroScan® for the follow-up of patients with CHB after 12 months of antiviral therapy.
MATERIALS AND METHODS
Study population and data collection
Patients aged 18 years and older who were positive for hepatitis B surface antigen positivity for more than 6 months and had an HBV-DNA level > 2000 IU/mL were included in the study. Written informed consent was obtained from all participants. The exclusion criteria were established as the presence of cirrhosis, alcohol consumption > 140 g/week for females and > 210 g/week for males, and hepatitis C, hepatitis D, and/or HIV coinfections. The baseline characteristics including patient demographics, body mass index, comorbidities, LSM and CAP via transient elastography (FibroScan®), liver ultrasound, HBV serology, platelet count, alanine aminotransferase (ALT), and HBV viral load were collected.
Evaluation of liver status and antiviral therapy
All patients underwent liver biopsy and FibroScan® before initiating antiviral therapy. There was a maximum interval of 2 weeks between the liver biopsy and the FibroScan®. Transient elastography was performed by a certified operator, using the M probe for patients with skin to capsule distance < 2.5 cm or an XL probe for patients with skin to capsule distance > 2.5 cm. Patients were fasted for > 2 h before the FibroScan®. At least 10 successful measurements were performed and recorded.[16]
Fibrosis stage by LSM and steatosis by CAP were investigated on FibroScan® for MASLD and MASH. Patients with obesity or diabetes with a CAP value > 240 dB/m were diagnosed with MASLD. Patients with a normal body mass index and patients without diabetes who had at least two risk factors for metabolic dysfunction were also diagnosed with MASLD. Patients with MASLD and concomitant necroinflammation in the liver were diagnosed with MASH. Necroinflammation was defined as LSM ≥ 7.2 kPa in patients with MASLD or LSM > 5.5 kPa in patients with liver injury (histologic and/or ALT > non-specific uptake).
The study protocol was approved by the Ethics Committee of Dicle University (Protocol number: 2022/261). Our trial was registered to Clinical Trials as a completed trial retrospectively, and the trial registration ID is NCT06573190.
Statistical analysis
The SPSS 21.0 statistical software for Windows (IBM Corp., Armonk, NY, United States) was used for the statistical evaluation of the research data. The measurable variables were presented as mean ± standard deviation, while the categorical variables were presented as number (n) and percentage (%). Spearman’s rho correlation analysis was performed to determine the relationship between the variables. The hypotheses were bidirectional, and P ≤ 0.05 was considered statistically significant.
RESULTS
Demographics
A total of 70 patients from Diyarbakir, Batman, Mardin, and Sanliurfa were included in this prospective, multicenter study. The mean age of the patients was 37.1 years, with a predominance of males (49 patients, 70.0%).
Comparison of histopathologic evaluation and elastography
Two patients (2.9%) who underwent biopsy yielded insufficient tissue for histopathological evaluation. The concordance rate between elastography and histopathological results was 97.1% in the 68 patients who underwent biopsy (P < 0.001). In 2 cases (2.9%), the fibrosis value was higher than the liver biopsy result. In 66 patients (97.1%), the liver fibrosis score was ≥ 2 or the hepatic activity index was ≥ 6. According to these results, all patients began antiviral treatment because they met the reimbursement criteria in our country.
Evaluation of the liver before and after antiviral therapy
All patients began tenofovir disoproxil fumarate (TDF) treatment. Before treatment, 19 patients (27.1%) were diagnosed with MASLD and 6 patients (8.6%) with MASH. The mean CAP value of all patients, patients with MASLD, and patients with MASH was 224 dB/m, 275 dB/m, and 291 dB/m, respectively. The mean LSM was 7.2 kPa in the patients before antiviral therapy and 7.1 kPa at the 12-month follow-up. For the 2 patients with insufficient liver biopsy material, the mean LSM was 8.4. HBV-DNA was > 2000 IU/mL, mean ALT level was 55.1 IU/L, and mean low-density lipoprotein-cholesterol (LDL-C) level was 93.6 mg/dL in all patients (Table 1).
| Variables | Results |
| Age, years, mean (SD, range) | 37.1 (18.5, 22.0-62.0) |
| Underlying diseases (n) | DM (5), HT (5) |
| Male, n (%) | 49 (72.0) |
| ALT in IU/mL (mean ± SD) | 55.1 ± 30.4 |
| HBV-DNA, mean | 5.65 × 107/mm3 |
| Fibrosis ISHAK score, mean | 2.1 |
| LSM by FibroScan® in kPa, mean | 7.2 |
| CAP by Fibroscan® in dB/m, mean | 224 |
| Triglycerides in mg/dL | 194.6 ± 40.2 |
| Total cholesterol in mg/dL | 215.4 ± 40.2 |
| LDL-C in mg/dL | 93.8 ± 21.6 |
| HDL-C in mg/dL | 54.8 ± 8.2 |
| BMI, mean | 26.7 |
| Statin use, n (%) | 2 (2.9) |
| Alcohol use*, n (%) | 4 (5.9) |
At the 12-month follow-up (Table 2), the MASLD rate decreased to 25.7% (P = 0.064). No change in the MASH rate was detected. HBV-DNA was undetectable in 95.6% of patients, and the ALT level was within normal ranges in 84.3% of patients.
| Baseline variable | Baseline | 12-month follow-up | P value |
| MASLD, % (n) | 27.1 (19) | 25.7 (18) | 0.064 |
| MASH, % (n) | 8.6 (6) | 8.6 (6) | N/A |
| Mean ALT | 54.9 IU/mL | 43.1 IU/mL | < 0.001 |
| Mean HBV-DNA | 5.65 × 107 | 2.2 × 102 | < 0.001 |
| Mean CAP, n = 66 | 224.7 | 221.1 | 0.003 |
| LSM by FibroScan® in kPa, mean | 7.2 | 7.1 | N/A |
| Triglycerides in mg/dL | 194.6 ± 40.2 | 188.1 ± 31.9 | 0.069 |
| Total cholesterol in mg/dL | 215.4 ± 40.2 | 211.6 ± 31.1 | 0.058 |
| LDL-C in mg/dL | 93.8 ± 21.6 | 75.6 ± 17.6 | 0.034 |
| HDL-C in mg/dL | 54.8 ± 8.2 | 55.1 ± 10.1 | 0.076 |
Lipid profile and hepatosteatosis
Lipid profiles were evaluated before and after antiviral treatment. Triglycerides levels decreased (194.6 ± 40.2 mg/dL vs. 188.1 ± 31.9 mg/dL, P = 0.069), total cholesterol levels decreased (215.4 ± 40.2 mg/dL vs. 211.6 ± 31.1, P = 0.058), LDL-C levels decreased significantly (93.8 ± 21.6 vs. 75.6 ± 17.6, P = 0.034), and high-density lipoprotein-cholesterol (HDL-C) levels increased slightly (54.8 ± 8.2 vs. 55.1 ± 10.1, P = 0.076). Notably, only the decrease in the LDL-C level reached statistical significance. When patients with MASLD and MASH were evaluated separately, significant decreases in triglycerides, HDL-C, and LDL-C levels were found in patients with MASLD (Table 3).
| Lipid profile | Baseline | 12-month follow-up | P value |
| Patients with MASLD | |||
| Triglycerides in mg/dL | 224.4 ± 22.3 | 215.7 ± 17.8 | 0.041 |
| Total cholesterol in mg/dL | 228.8 ± 29.3 | 225.7 ± 21.1 | 0.072 |
| LDL-C in mg/dL | 98.6 ± 19.3 | 81.9 ± 15.8 | 0.034 |
| HDL-C in mg/dL | 51.2 ± 9.1 | 53.8 ± 8.4 | 0.033 |
| Patients with MASH | |||
| Triglycerides in mg/dL | 228.4 ± 28.4 | 227.7 ± 27.1 | 0.081 |
| Total cholesterol in mg/dL | 226.1 ± 23.8 | 225.9 ± 20.9 | 0.078 |
| LDL-C in mg/dL | 99.5 ± 16.6 | 96.9 ± 13.6 | 0.094 |
| HDL-C in mg/dL | 50.9 ± 8.1 | 51.6 ± 7.8 | 0.088 |
DISCUSSION
Currently, high virologic response rates are achieved with high resistance barrier nucleos(t)ide antiviral therapies that suppress inflammation and reduce fibrosis progression.[2,17] Despite antiviral therapy, the risk of cirrhosis and HCC persists, and patients still require follow-up. In addition to viral injury, comorbid factors such as metabolic syndrome and MASLD/MASH play an important role in the progression of liver fibrosis and carcinogenesis. Although severe hepatosteatosis has been shown to accelerate the progression to fibrosis, the effect of milder steatosis is still unknown.[6,18] However, Con et al. observed that concomitant MASLD does not accelerate the progression to fibrosis in the short-term and medium-term in patients with CHB but without cirrhosis.[10]
In a very recent study, Huang et al. followed 11,502 treatment-naïve patients with CHB but without cirrhosis for 5.3 years.[19] They reported that patients in the metabolic dysfunction group were older and had lower HBV-DNA. The metabolic dysfunction group was also at higher risk for cirrhosis and cirrhosis complications. Newly occurring diabetes mellitus during follow-up also increased the risk of complications due to cirrhosis. Fatty liver was associated with a lower risk of cirrhosis and complications at 5 years. Among patients with fatty liver, those with MASLD showed a higher risk of cirrhosis than those without metabolic dysfunction.[19]
In patients with CHB, it is of great importance to evaluate liver fibrosis before initiating antiviral therapy to monitor the change in fibrosis during long-term follow-up. Biopsy is the gold standard for the evaluation of liver necroinflammation and fibrosis. However, there are several limitations including sampling errors, patient dissatisfaction, procedural difficulty, cost, bleeding and other complications, and differences in assessment.[1] Therefore, more studies and guidelines have been developed and suggested non-invasive tests and transient elastography as an alternative to guide treatment decisions before antiviral therapies and to monitor their efficacy afterwards.[1,20] Moreover, liver biopsy does not provide information on the status of fibrosis (i.e. progressing, regressing, or stable) and only provides instantaneous information.[21]
In a single-center study, the diagnostic efficacy of FibroScan® was compared to liver biopsy in 1185 patients with CHB.[14] A positive correlation was found between the degree of inflammation and LSM values. Liver inflammation can be evaluated as well as liver fibrosis by FibroScan®.[14] Moreover, a recent meta-analysis showed that FibroScan® has good sensitivity and specificity for the detection of steatosis and fibrosis.[22] The authors also argued that FibroScan® is cost-effective, reproducible, and useful for patient follow-up. In another study, FibroScan® was also used validation of tests used in the diagnosis of fatty liver disease.[23] The use of FibroScan® in the assessment of MASLD/MASH in many patient groups, including CHC, HIV-infected, diabetes and obstructive sleep apnea, indicates its increasing use worldwide.[24–27]
In our country, the reimbursement system for oral antiviral treatment is like the criteria in the AASLD/EASL and APASL guidelines.[2,28,29] Oral antiviral treatment requirements are generally covered by our insurance system. The most patients at follow-up do not want to undergo a repeat liver biopsy. Therefore, at the 12-month follow-up, we only evaluated the effect of antiviral therapy by Fibroscan®. Moreover, we showed that the correlation between biopsy and Fibroscan® was quite high before therapy. We found that 27.1% of the patients had MASLD and 8.6% had MASH. The mean CAP values for all patients, patients with MASLD, and patients with MASH were 224 dB/m, 275 dB/m, and 291 dB/m, respectively, with a mean LSM level of 7.2 kPa. Con et al. reported that LSM was 15% higher in patients with CHB and MASLD compared to those without MASLD.[10] Moreover, LSM values increased as hepatis B viral load increased. They also showed that LSM values decreased in patients with and without MASLD during follow-up after therapy.
We observed a decrease in the MASLD rate after 12 months of antiviral treatment, but the rate of MASH did not change. Several studies have reported a paradox that concurrent hepatic steatosis appears to provide viral suppression and increase the hepatitis B surface antigen seroconversion rate.[7,9,18] However, it is generally accepted that hepatic steatosis causes or triggers fibrosis.[6] These conflicting findings suggest a complex association with CHB, especially after the redefinition of fatty liver as MASLD. Even if the presence of hepatosteatosis leads to reduced viral activity and regression of liver injury, the presence of metabolic risk factors such as diabetes may increase the risk of HCC.[30,31]
A recent study reported that 483 of 1613 patients with CHB had MASLD (29.9%), and the cumulative incidence of HCC was higher in those with MASLD in the 5.02-year follow-up period.[32] Similarly, in a health screening program with a large number of participants (336,866 adults, aged ≥ 30 years), 36.4% were diagnosed with MASLD, 14.6% had CHB, 1.1% had chronic hepatitis C (CHC), and 0.3% had CHB and CHC coinfection. The presence of MASLD in patients with CHB or CHC who received antivirals during follow-up was reported to be associated with an increased risk of cirrhosis and HCC.[33] However, the risk of cirrhosis and HCC was higher in those with only CHB or CHC than in those with MASLD alone. The authors concluded that antiviral treatment of chronic viral hepatitis had priority before addressing MASLD.[33]
Liver transplantation may be unique option because of the bad scenarios mentioned above. If MASLD/MASH is present before transplantation, it may recur or develop de novo. In one study, the diagnosis of recurrent MASH by FibroScan® after liver transplantation was compared with liver biopsy. In this study, a strong correlation was shown when post-transplant LSM values were < 8 kPa. They concluded that FibroScan® could be an effective non-invasive tool to stage liver fibrosis recurrence among patients transplanted for MASH cirrhosis, and specifically to screen for those at no need of biopsy.[34]
It is noteworthy that patients with MASLD/MASH in our study had higher lipid levels. However, there appeared to be a mild lipid profile abnormality in all patients. It has been suggested that dyslipidemia is indirectly related to the development of HCC through hepatic fibrosis in patients with chronic viral hepatitis. It is also well known that dyslipidemia causes steatohepatitis, and severe hepatic steatosis increases the risk of liver fibrosis in patients with CHB.[19,35] Even in one study, dietary inflammatory index in relation to the progression of hepatic steatosis and liver fibrosis was evaluated by FibroScan®.[36] There are several conflicting results with FibroScan® measurements in obese individuals with more accurate results in those with lower BMI.[37,38] In a recent study, intraoperative liver biopsy was compared with FibroScan® in patients undergoing bariatric surgery and acceptable data were obtained. It was shown that the data were better in patients with BMI < 44.4 kg/m2.[39]
In a recent network meta-analysis, it was reported that TDF may reduce the levels of lipid profiles, especially total cholesterol levels. This effect was not evident among the patients with CHB receiving tenofovir alafenamide, entecavir, or no treatment.[40] When all patients in our study were evaluated at the 12-month follow-up during TDF treatment, only LDL-C levels significantly decreased, whereas triglycerides, HDL-C, and LDL-C levels decreased after the subgroup analysis of patients with MASLD. This improvement in lipid profile may be because of TDF. Considering its renal toxicity and effects on bone mineral density, TDF should be used with caution, especially in elderly patients. However, TDF may be preferred in patients with an impaired lipid profile and those at risk of atherosclerotic heart disease.[40]
The advantages of this study included the prospective, multicenter design. All patients also underwent biopsy at baseline. The limitations of the study were the small number of patients who represented only one region of the country, and the short follow-up period. The 24th month follow-up of the patients and their measurements by FibroScan® are ongoing.
In conclusion, the association of metabolic disfunction and MASLD/MASH in patients with CHB is increasing. These risk factors should be proactively investigated in treatment-naïve patients during follow-up. FibroScan® is a useful, non-invasive alternative to biopsy for the diagnostic evaluation and treatment follow-up of these patients.
DECLARATIONS
Acknowledgments
We thank Nobel Pharmaceuticals and Southeast Neurology and Infectious Diseases Society for financial support.
Author contributions
Celen MF served as the principal investigator, constructed the hypothesis/idea of the research, wrote the manuscript, prepared the application for the Ethics Committee, and performed the Fibroscan® measurements; Mermutluoglu C, Akgül F, Cakmak P, Cakirca TD collected the data, took responsibility for the patient follow-up, and wrote the manuscript; Yildiz I performed the statistical analysis and writing of the manuscript; Tasova Y and Bayindir Y constructed the hypothesis/idea of the research, wrote the manuscript, and prepared the application for the Ethics Committee; All authors read and approved the final manuscript.
Source of fund
Nobel Pharmaceuticals, and Southeast Neurology and Infectious Diseases Society
Use of large language models, AI and machine learning tools
None declared.
Informed consent
Written informed consent was obtained from all participants.
Conflict of interest
All the authors report no relevant conflicts of interest for this article.
Data sharing statement
Technical appendix, statistical code, and dataset available from the corresponding author at yasarb44@hotmail.com.
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