Revitalizing liver health: Human placental extract shows promise in chronic liver disease management

Abstract

This editorial provided commentaries on an article titled "Liver function improvement after human placental extract injections in patients with chronic liver disease: Thirty case reports". The first clinical application of an innovative therapeutic protocol was comprehensively described in this case report by Lee, in which 30 patients with chronic liver disease (CLD) received intravenous administration of 10 mL human placental extract (HPE). Notably, significant improvements in liver function could be observed in these patients, which underscored the potential of this novel treatment for CLD management. However, the rising prevalence of CLD around the world underscored the limitations of conventional therapies (such as antiviral agents and lifestyle modifications) in addressing advanced fibrosis or metabolic dysfunction-associated steatotic liver disease. Additionally, emerging regenerative therapies (including HPE) have garnered more attention due to their bioactive components, which could modulate the hepatic microenvironment based on antioxidant, anti-inflammatory, and pro-regenerative mechanisms. Although the existing evidence remains relatively lacking, the multi-targeted action of HPE highlights its potential as a novel therapeutic strategy. Overall, this editorial outlines the research advancements of HPE, alongside the critical analysis of existing limitations and the proposal of future research directions.

Key Words: Human placental extract; Chronic liver disease; Liver fibrosis; Regenerative medicine; Antioxidant; Clinical translation

Core Tip: An innovative intervention involving intravenous injection of human placental extract was introduced in a recent case report from Danann Medical Clinic, which aimed to improve the liver functions of chronic liver disease patients. However, the study was restricted by the issues, including a small sample size, absence of a control group, and insufficient long-term safety data, and the mechanistic underpinnings and generalizability of therapeutic efficacy required further validation.

INTRODUCTION

Chronic liver disease (CLD) has been considered a major public health challenge globally, and its most prevalent etiologies are composed of metabolic dysfunction-associated fatty liver disease, hepatitis B virus, hepatitis C virus, and alcohol-related liver disease. It is indicated by epidemiological data that approximately 1.5 billion individuals worldwide are affected by various stages of CLD, of whom 20%-30% may progress to hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC), which substantially aggravate the disease-related morbidity and mortality[1-3]. However, current therapeutic approaches are restricted by suboptimal clinical efficacy, frequent drug resistance, and significant adverse effects[4], which underscores the urgent need for the development of safe and effective novel therapeutics.

Emerging evidence highlights the potential therapeutic values of human placental extract (HPE) during the management of chronic liver conditions, including hepatitis, steatotic liver disease, hepatic fibrosis, and cirrhosis. Besides, experimental and preclinical studies suggested that its mechanisms involved multifaceted biological effects, which were composed of anti-inflammatory activity, oxidative stress mitigation, and tissue-repair promotion. Therefore, HPE could serve as a potential multi-targeted approach distinct from conventional single-mechanism therapies, such as antivirals (which target specific pathogens) or lifestyle modifications (which primarily address metabolic drivers). Overall, the current options remain suboptimal for the treatment of patients with advanced fibrosis or metabolic dysfunction-associated steatotic liver disease (MASLD), while this integrated action profile could position HPE as a candidate to fill the critical therapeutic gap, thus providing novel insights for the optimization of liver disease management strategies.

RESEARCH PROGRESS OF HPE IN THE TREATMENT OF CLD

HPE is a natural therapeutic agent utilized in Japan for liver disease management since the 1950s, and it has historically lacked robust clinical validation. The human placenta constitutes a rich repository of bioactive molecules, including hepatocyte growth factor (HGF), epidermal growth factor, transforming growth factor-α, L-tryptophan-based antioxidants, and steroid hormones[5-7].

Notably, HPE has been confirmed to exhibit antioxidant activity, and it is demonstrated that HPE could improve the oxidative stress primarily through Nrf2 pathway activation, which could contribute to the significant enhancement in superoxide dismutase and glutathione levels and activity. Besides, this mechanism could effectively scavenge reactive oxygen species and alleviate the accumulation of lipid peroxidation markers (malondialdehyde) and nitric oxide[8-10].

HPE has demonstrated potent anti-inflammatory effects in the liver, and it is revealed by preclinical studies that HPE could attenuate hepatic inflammation based on several key mechanisms: (1) Downregulation of intercellular adhesion molecule-1 expression, which serves as a critical mediator of leukocyte transmigration[11,12]; and (2) Suppression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, alongside the modulation of the anti-inflammatory cytokine IL-10 to restore immune homeostasis[8,9,11,13].

Besides, HPE can improve liver fibrosis and promote liver cell regeneration, and it exhibits multi-target antifibrotic activity based on TGF-β1 pathway inhibition and alleviation of collagen synthesis and extracellular matrix deposition[10,14,15]. Concurrently, as demonstrated by Wolf et al[16], the regenerative potential of HPE stems from endogenous HGF-mediated mitogenic activation in primary hepatocytes[16]. Moreover, the proliferative effects of HPE across diverse liver cell lineages have been confirmed by in vitro models with the application of WB-F344 rat hepatocytes, T-HSC/Cl-6 human hepatic stellate cells, and HepG2 hepatoma cells[8,15,17].

A recent landmark case series by Lee[18] investigated intravenous HPE administration (10 mL/dose, 1–2 weekly) in 30 CLD patients[18], and it could be indicated that HPE treatment significantly reduced the alanine aminotransferase and aspartate aminotransferase levels of patients and improved the imaging manifestations of fatty liver, which exhibited high clinical significance. Notably, no significant side effects or adverse reactions were observed during this research, which could indicate the excellent safety of HPE treatment, while the safety performance was crucial for the promotion and application of new therapies. Additionally, the authors claimed that the study was conducted without the consent of individual patients, in which the post-treatment data was utilized in the study. According to the institutional and privacy guidelines, the authors did not share any patient-identifiable information, suggesting that the ethical aspects of the study required further discussion. Furthermore, the conclusive clinical interpretation and generalizability of the findings were significantly restricted by the methodological limitations, including the small sample size, an uncontrolled (non-randomized, lacking a comparator group) design, absence of blinding, relatively short duration of follow-up, and absent long-term safety data.

CURRENT LIMITATIONS IN HPE RESEARCH

Current research on HPE faces critical limitations, which underscores the urgent need for resolution. First, the existing evidence base predominantly relies on animal studies and small-scale clinical case reports, which is lacking in robust support from high-quality, multicenter randomized controlled trials. Functionally, this gap directly undermines the reliability of research conclusions and hinders clinical translation. Second, systematic monitoring and evaluation systems for safety risks still remain underdeveloped, particularly for the immunogenicity (including sensitization and potential for autoimmune activation), the risk of transmitting blood-borne pathogens despite processing, the potential for allergic reactions (both acute and delayed), and the impact of significant variability in HPE composition between batches/sources caused by differences in placental donors, collection methods, and extraction protocols, and these issues leave the safety boundaries of clinical applications undefined. Third, comprehensive ethical frameworks and stringent regulatory oversight of the placental tissue source (ensuring informed consent, traceability, and ethical procurement), the processing of relevant samples (standardization, sterility, viral inactivation validation), and clinical application are still under development, which need to be explicitly integrated into the research and development pathway.

FUTURE DIRECTIONS

To address these challenges, future studies should seek to narrow the gap between basic research and clinical application of HPE. It is necessary to establish robust regulatory pathways and ethical guidelines for human-derived biological products, and to ensure the traceable and ethically sourced material, alongside the standardized and validated manufacturing processes. In order to evaluate the efficacy in reversing hepatic fibrosis and improving long-term prognosis across etiologically diverse chronic liver disease populations, the design of rigorous multicenter phase II/III clinical trials with adequate power (sample size), randomization, appropriate control groups (e.g., placebo or standard of care) should be prioritized, alongside the blinding methods and the extension of follow-up periods (e.g., 1-2 years minimum). Besides, the key endpoints should be composed of histological improvement (e.g., liver biopsy), non-invasive fibrosis markers, hard clinical outcomes (e.g., decompensation events, HCC development, mortality), and comprehensive safety profiles. Additionally, it is necessary to clarify the dose-response relationships and personalized treatment strategies. Moreover, a comprehensive safety assessment framework (specifically focusing on immunogenicity, long-term tolerability, and batch consistency) should be constructed to standardize clinical practices. Crucially, research should deeply explore the potential synergistic or additive effects of HPE in combination with established therapies (e.g., antivirals for viral hepatitis, lifestyle interventions for MASLD, or emerging antifibrotics), which aims at the evaluation of the applicability of HPE for the enhancement of efficacy or mitigation of adverse effects.

CONCLUSION

Based on multitarget modulation of the hepatic cellular microenvironment, HPE could serve as an innovative therapeutic strategy for chronic liver disease management, and it demonstrates integrated antioxidant, anti-inflammatory, antifibrotic, and pro-regenerative properties. Notably, although current evidence remains preliminary, the clinical potential of HPE has gained significant scientific attention. Future research must prioritize the validation of long-term safety within robust ethical and regulatory frameworks, exploration of synergistic effects with conventional therapies, alongside the resolution of challenges related to product standardization and composition variability, which can ultimately translate the laboratory breakthroughs into safe and effective bedside applications.

ACKNOWLEDGEMENTS

We express our sincere gratitude to the reviewers for their invaluable comments. These insights have significantly contributed to the enhancement of the manuscript.