Editor's Note: The liver is a powerful organ with complex physiological structures and functions. Liver fibrosis is a dynamic pathological process associated with various chronic liver diseases, ultimately leading to cirrhosis. In cirrhosis, the liver not only becomes harder but also shrinks in size, with imaging showing changes in the liver's appearance accompanied by alterations in hepatic hemodynamics. Recently, at the 10th Beijing Hepatology Academic Annual Conference in 2024, Hepatology Digest invited Dr. Dong Ji from the Fifth Medical Center of the Chinese PLA General Hospital to discuss the latest insights and strategies on liver fibrosis reversal. The interview has been compiled into this article for readers to reference.Hepatology Digest: What key research advancements have been made in the field of liver fibrosis reversal in recent years, and how have these advancements impacted clinical practice?
Dr. Dong Ji: The process of liver fibrosis is quite complex, involving multiple mechanisms. Despite numerous studies, no chemical drugs have been approved for the treatment of liver fibrosis due to the complexity of the targets involved.
In contrast, traditional Chinese medicine (TCM) has achieved high levels of evidence-based success in this area. For example, our articles published in JOH and research projects such as the “12th Five-Year” and “13th Five-Year” National Major Infectious Disease Projects, involving treatments like Fuzheng Huayu Capsules, Anluo Huaxian Pills, and Fufang Biejia Ruangan Tablets, have provided strong evidence-based proof that TCM has made significant progress in anti-fibrosis treatment.
Additionally, the dual-therapy strategy that combines TCM anti-fibrosis treatment with antiviral treatment can further increase the reversal rate of liver fibrosis and effectively reduce the incidence of liver cancer, positively impacting clinical practice.
Hepatology Digest: What are the specific mechanisms of liver fibrosis reversal? What challenges do we currently face in achieving fibrosis reversal, and what effective strategies have you and your team employed?
Dr. Dong Ji: The core mechanism of liver fibrosis progression involves the activation of hepatic stellate cells. This activation process occurs through two main pathways: First, paracrine signaling, where hepatic parenchymal cells, sinusoidal endothelial cells, and Kupffer cells produce inflammatory cytokines in response to various etiological stimuli, which then promote the activation of hepatic stellate cells. Second, autocrine signaling, where already activated hepatic stellate cells further activate themselves, leading to a cascade of reactions that ultimately cause extracellular matrix deposition in liver tissues, resulting in fibrosis progression and cirrhosis.
The main challenge in treatment is how to effectively intervene in this complex activation process. Our strategy is dual-targeted therapy: on the one hand, treating the underlying cause to prevent or reduce paracrine activation of hepatic stellate cells, and on the other hand, providing anti-fibrosis treatment to inhibit the autocrine activation of these cells. Through these two approaches, we aim to halt the progression of liver fibrosis.
Under the leadership of Professor Yang Yongping, our team has conducted major research projects during the “12th Five-Year” and “13th Five-Year” National Major Infectious Disease Projects. The results demonstrate that the dual-therapy strategy, combining antiviral treatment with TCM, can significantly increase the reversal rate of liver fibrosis and reduce the incidence of liver cancer. Specifically, the incidence of liver cancer decreased by 50%, and liver-related mortality decreased by 90%.
Hepatology Digest: Given the differences in the degree and etiology of liver fibrosis among patients, how important is individualized treatment in fibrosis reversal? How do you tailor treatment plans based on the specific circumstances of each patient?
Dr. Dong Ji: Precision medicine and targeted therapy are key directions in modern medicine. Similar to the traditional Chinese medicine (TCM) principle of individualized treatment, modern Western medicine also emphasizes treating the disease based on its cause. For example, for patients with viral hepatitis, the primary approach is etiological treatment, i.e., antiviral therapy. For alcoholic liver disease, the patient needs to abstain from alcohol. Non-alcoholic liver disease requires treatment for metabolic syndrome and obesity. For chronic liver disease caused by drug-induced liver injury, discontinuing the suspected medication and providing appropriate treatment is necessary. Since the causes of liver fibrosis vary, the treatment plans we provide are also entirely different.
In anti-fibrosis treatment, TCM shows significant advantages. TCM emphasizes a holistic approach, akin to multi-targeted and multi-faceted treatment from a modern medical perspective, providing effective treatment for fibrosis reversal. Therefore, although the etiological treatments are diverse, TCM currently plays a crucial role in anti-fibrosis treatment. Although there are no specific Western drugs available yet, with ongoing research, we anticipate the development of targeted chemical drugs to effectively inhibit fibrosis progression, and we look forward to the emergence of newer and better treatments.
Hepatology Digest: What role does antiviral therapy, as the cornerstone of chronic hepatitis B treatment, play in the reversal of liver fibrosis? How do you balance antiviral treatment with anti-tumor therapy in liver cancer patients?
Dr. Dong Ji: Etiological treatment is critical in liver fibrosis reversal. For viral hepatitis, which accounts for the majority of cases, antiviral therapy is particularly important. The first-line drugs we currently recommend include entecavir, tenofovir, and interferon, all of which are effective antiviral therapies.
The primary goal of antiviral therapy is to achieve complete virological response, meaning undetectable HBV DNA levels. The current detection limit is 10 IU/mL or 20 IU/mL, but with advancements in technology, this threshold may be lowered to 5 IU/mL or even zero, which is the goal we are continuously striving for.
If antiviral therapy does not achieve a complete virological response (i.e., HBV DNA levels remain above the detection limit), we need to adjust the treatment plan promptly. For example, if HBV DNA is still detectable after one or two years of antiviral therapy, we must adjust the strategy to achieve a complete virological response, underscoring the importance of antiviral treatment.
In clinical practice, we encounter many related cases. A typical example is liver cancer patients who, after developing the disease, experience a reactivation of previously undetectable HBV DNA, leading to low-level replication and fluctuating liver inflammation, which impacts anti-tumor treatment. Therefore, antiviral therapy is the primary and necessary goal that must be achieved, and it is relatively straightforward to do so. Once this is accomplished, we can proceed with anti-tumor treatment.
Hepatology Digest: What challenges remain in raising public awareness of liver fibrosis and its reversal? How can we better convey scientific and accurate knowledge to the public to help them understand the disease correctly?
Dr. Dong Ji: In 2016, the World Health Organization (WHO) set the goal of eliminating viral hepatitis as a public health threat by 2030. Currently, we face two major challenges: first, the low treatment rate—many patients know they have hepatitis B or C but do not actively seek treatment at hospitals; second, the low diagnosis rate—many patients are unaware of their condition and do not proactively go to the hospital for screening.
To improve public awareness, we can focus on the following points:
- Increase scientific outreach and public education, so more people understand these diseases, know that hepatitis C can be cured, and hepatitis B can be controlled.
- Educate the public about transmission routes and when they might be at risk, so they can promptly seek screening at hospitals.
- From the hospital’s perspective, increase screening rates. For invasive diagnostics or treatments, hospitals should mandate testing for HBV, HCV, HIV, and syphilis. For high-risk populations who do not undergo invasive diagnostics or treatments, doctors should recommend screening for viral hepatitis, especially for those with a family history of hepatitis B, a history of blood transfusion, or surgery.
- For patients who have already received treatment and whose condition is stable, they should not discontinue medication on their own. They should consult their doctor based on their actual condition to decide whether to continue treatment. We have encountered many cases where patients, after achieving a stable condition indistinguishable from healthy individuals, believe there is no need to continue medication and stop on their own, resulting in disease recurrence and progression—a very unfortunate outcome.
- For older patients or those with comorbidities such as obesity, excessive alcohol consumption, or frequent use of other medications, lifestyle adjustments should be made to reduce these factors’ impact on liver damage.
