Editor's Note: HBV infection is a major cause of chronic hepatitis B (CHB), cirrhosis, liver failure, and hepatocellular carcinoma. Despite the development of new drugs and advancements in antiviral therapy, a complete cure for CHB remains a clinical challenge. The burden of liver disease in China is still heavy, and the implementation of high-quality liver disease management is urgently needed. This involves a comprehensive approach that includes enhanced public education, convenient screening and monitoring, empowerment of primary healthcare, optimization of doctor incentives, refined data management, and scientifically sound prevention and treatment strategies. Recently, Dr. Sujun Zheng from Beijing You An Hospital, Capital Medical University, provided a systematic overview of the exploration and progress in comprehensive liver disease management during an academic exchange. The following is a summary of the key points shared.Epidemiological Status
1. The Global Burden of Chronic Liver Disease is Heavy and Increasing
In 2017, there were 2.14 million liver-related deaths worldwide (range: 2.06 million to 2.30 million), an 11.4% increase compared to 2012. Among these, liver cancer deaths increased by 16.0%, and cirrhosis deaths by 8.7%. Viral hepatitis remains the most common cause of liver-related deaths, while metabolic-associated fatty liver disease (MAFLD) is the fastest-growing factor contributing to liver-related mortality and morbidity.
2. High Prevalence and Burden of Fatty Liver Disease Globally
The global prevalence of MAFLD ranges from 25.1% to 44.37%, with China at 29.71%. Among overweight individuals, the prevalence of MAFLD and metabolic-associated steatohepatitis (MASH) is 70.0% and 33.5%, respectively. In obese individuals, the prevalence of MAFLD and MASH is 75.3% and 33.7%, respectively. In patients with type 2 diabetes mellitus (T2DM), the prevalence of MAFLD, MASH, and advanced liver fibrosis is 55.5%, 37.3%, and 17.0%, respectively.
3. Mortality Rate of Hepatitis B-Related Liver Diseases
The total number of liver disease deaths caused by hepatitis B in China decreased from 229,000 in 1990 to 162,000 in 2019, a decline of 29.13%. Between 1990 and 2019, mortality rates for hepatitis B-related acute hepatitis, cirrhosis, and other chronic liver diseases and cancer decreased by 74.83%, 34.71%, and 23.34%, respectively. The age-standardized mortality rate showed a downward trend. However, from 2015 to 2019, the number of cancer deaths due to hepatitis B increased by 7.05%. The mortality rate among males was higher than that among females (mortality ratio: 2.2~3.0), and the risk of death among cancer patients increased with age.
Comprehensive Management of Liver Diseases
1. Screening for MASH Patients to Prevent MAFLD-Related Cirrhosis
The disease spectrum of MAFLD includes simple fatty liver, MASH, cirrhosis, and hepatocellular carcinoma. The risk of MASH progressing to cirrhosis is five times higher than that of simple fatty liver.
Currently, there is a lack of non-invasive diagnostic methods for steatohepatitis. Histopathological diagnosis of steatohepatitis requires the presence of hepatic steatosis, hepatocyte injury, and lobular inflammation. Serum alanine aminotransferase (ALT) levels are a sensitive marker for monitoring hepatocellular inflammation but cannot rule out the possibility of advanced MASH solely based on normal ALT levels, nor does elevated ALT necessarily indicate MASH. As the disease progresses, MASH patients exhibit significantly elevated levels of inflammatory markers such as CRP, ferritin, TNF-α, IL-6, and IL-8 in the serum, but these are susceptible to various interference factors and do not meet clinical diagnostic requirements. Currently, there are no satisfactory non-invasive diagnostic indicators, imaging parameters, or diagnostic techniques due to the complex factors influencing hepatic inflammation and the scarcity of inflammation-related specific markers.
Cytokeratin (CK) belongs to the intermediate filament protein (IFP) family, forming part of the cytoskeleton. CK18-M30 is a specific marker of hepatocyte apoptosis, while CK18-M65 is a marker of hepatocyte death. Studies have shown that CK18 is an independent predictor of MASH and can differentiate between MAFLD and MASH. CK18-M30 can effectively diagnose MASH.
A global multicenter study involving 1,008 participants from 14 research centers in 8 countries, including 153 with simple fatty liver and 855 with MASH, found that the median CK18-M30 level in MASH patients was significantly higher than in those with simple fatty liver. The AUROC for CK18-M30 in diagnosing MASH was 0.750 (95% CI: 0.714~0.787). The optimal cutoff value was 275.7 U/L, with sensitivity, specificity, and positive predictive values of 55%, 86.9%, and 59%, respectively.
Dr. Sujun Zheng’s previous research found that CK18 M30/M65 could predict the prognosis of HBV-related acute-on-chronic liver failure (ACLF).
2. Actively Treating Hepatitis B, Screening for Liver Fibrosis, and Preventing and Reducing the Occurrence of Liver Cancer
The 2021 consensus on secondary prevention of primary liver cancer identified the target populations and measures for tertiary prevention of HCC.
Biomarker-guided diagnostic and treatment strategies hold promise for improving the efficacy of treatment in patients with viral hepatitis. HBV virologic markers mainly include quantitative HBV DNA, quantitative HBV RNA, HBV genotyping, and viral strain mutations. HBV RNA is a direct downstream transcriptional product of covalently closed circular DNA (cccDNA) and reflects the number and transcriptional activity of intrahepatic cccDNA. Dr. Sujun Zheng’s team has conducted multiple studies on biomarker-guided diagnostic and treatment strategies.
One study evaluated the correlation between intrahepatic cccDNA and other serum viral markers and intrahepatic HBV DNA during 60 months of nucleos(t)ide analog (NA) therapy in HBeAg-positive CHB patients. Before NA therapy, the correlation between HBV DNA+RNA and cccDNA was superior to that of hepatitis B core-related antigen (HBcrAg). After NA therapy, the decline in HBV DNA+RNA was correlated with the decline in cccDNA, superior to that of HBV RNA, DNA, HBsAg, and HBcrAg, which showed no correlation.
Another study proposed a new concept of virologic response: the absence of detectable HBV DNA and HBV RNA represents a reduction or silencing of cccDNA. In a prospective cohort study conducted at You An Hospital involving 83 HBeAg-positive CHB patients, with a median follow-up of 108 months, a head-to-head comparison of HBV RNA, HBV DNA, HBsAg, and HBcrAg showed that HBV RNA levels at baseline, 6 months, and 12 months could predict HBeAg seroconversion.
Additionally, a study led by Dr. Sujun Zheng’s team, in collaboration with Dr. Fengmin Lu’s team at Peking University, included 74 HBeAg-positive CHB patients treated with entecavir or adefovir dipivoxil. The study found that baseline serum HBcrAg, HBsAg, and HBV RNA were more strongly correlated with the Ishak fibrosis score than APRI and FIB-4, with HBcrAg being the strongest correlate, followed by HBsAg and HBV RNA. However, after 60 months of NA antiviral therapy, these variables were no longer correlated with the degree of liver fibrosis. The study suggested that serum HBsAg, HBcrAg, and HBV RNA are potential markers for predicting significant liver fibrosis, and HBV RNA measurement is particularly valuable for monitoring liver fibrosis progression in HBeAg-positive CHB patients.
Since its launch in June 2022, China’s hepatitis B clinical cure project, “Star Program,” has involved 43 base hospitals, 356 sub-center hospitals, and a total of 408 hospitals across 28 provinces and cities. As of May 6, 2024, the project has screened 10,028 patients, with 6,593 successfully enrolled. Mid-term data analysis showed that 41.7% of the enrolled patients had moderate or higher levels of inflammation or fibrosis in their liver tissue, indicating an urgent need for antiviral therapy. At 48 weeks, the HBsAg clearance rate reached 32.2%, suggesting that these patients have a significant potential for clinical cure.
Dr. Xinyue Chen’s team found that interferon-induced HBsAg clearance resulted in a 9.66% relapse rate, and serum HBV RNA could serve as a potential predictor of HBsAg reversion.
In liver fibrosis and cirrhosis screening, Golgi protein 73 (GP73) has shown high diagnostic value. Serum GP73 levels are significantly correlated with increased fibrosis staging and markers indicating liver fibrosis and inflammation. GP73 has been identified as an independent predictor of significant fibrosis, defined as stage 2 or higher. When combined with transient elastography or magnetic resonance elastography, GP73 may outperform transient elastography alone in identifying MASH patients with fibrosis.
GP73 also holds diagnostic value for hepatic inflammation and fibrosis severity in hepatitis C. A retrospective dual-center study led by Dr. Sujun Zheng, involving 174 cases from the Fifth Medical Center of PLA General Hospital and 120 cases from You’an Hospital, found that serum GP73 levels significantly increased with worsening hepatic necroinflammatory activity and fibrosis staging in chronic hepatitis C patients.
3. Exploring Screening and Diagnostic Models for Early Liver Cancer
Multiple hematologic molecular markers can be used for early liver cancer screening. The early diagnosis rate of liver cancer in China is less than 30%, only one-third of Japan’s rate. Japan’s screening method, known as the “Three Tests for Liver Cancer + Ultrasound,” significantly improves the early diagnosis rate of liver cancer, offering valuable lessons for China.
In liver cancer risk prediction model research, the C-GALAD II liver cancer risk prediction model, based on clinical data from multiple hospitals in China, uses an algorithm incorporating age, gender, platelet count, total bilirubin concentration, and liver disease-specific markers such as alpha-fetoprotein (AFP), AFP-L3%, and des-gamma-carboxy prothrombin (DCP). The model’s performance in diagnosing liver cancer is superior to other models.
Conclusion
To reduce the burden of liver disease, comprehensive management of liver diseases must encompass the entire disease process, including screening, monitoring, treatment, and follow-up. Non-invasive screening techniques such as CK18-M30/M65 can identify MASH patients and prevent the progression of MAFLD to cirrhosis. Diagnostic and treatment strategies guided by serum biomarkers such as HBV RNA and GP73 hold promise for improving treatment outcomes in viral hepatitis patients and enhancing the diagnosis of liver fibrosis and cirrhosis. Early liver cancer screening using serum biomarkers like AFP, AFP-L3%, and DCP, as well as the C-GALAD II model, is expected to increase early diagnosis rates and improve cure rates.
