Zeng T, Huang SY, Chen JN, Pang JH, Chong YT, Li XH. Pathogenesis and clinical management of liver damage in porphyrias: Mechanisms and therapeutic approaches. World J Hepatol 2025; 17(9): 107705 [DOI: 10.4254/wjh.v17.i9.107705]
Corresponding Author of This Article
Xin-Hua Li, Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China. lixinh8@mail.sysu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Hepatol. Sep 27, 2025; 17(9): 107705 Published online Sep 27, 2025. doi: 10.4254/wjh.v17.i9.107705
Pathogenesis and clinical management of liver damage in porphyrias: Mechanisms and therapeutic approaches
Tao Zeng, Shu-Ying Huang, Jian-Ning Chen, Jia-Hui Pang, Yu-Tian Chong, Xin-Hua Li
Tao Zeng, Shu-Ying Huang, Jia-Hui Pang, Yu-Tian Chong, Xin-Hua Li, Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
Tao Zeng, Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, Sichuan Province, China
Jian-Ning Chen, Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
Co-first authors: Tao Zeng and Shu-Ying Huang.
Co-corresponding authors: Yu-Tian Chong and Xin-Hua Li.
Author contributions: Zeng T contributed to writing the original draft; Huang SY was involved in methodology and visualization; Zeng T and Huang SY contributed equally to this work and are designated as co-first authors. This decision reflects their balanced and complementary contributions essential for the completion of this study. Zeng T conducted the comprehensive literature search, and wrote the initial draft of the manuscript. This provided the foundational framework for the paper. Huang SY was responsible for the crucial data visualization, creating all figures and tables to effectively present the results. Furthermore, she meticulously revised and polished the manuscript for scientific accuracy, clarity, and language, which was vital for preparing the paper for submission. Both authors dedicated equal effort and intellectual input throughout the research and writing process. Chen JN and Pang JH contributed to investigation; Chong YT provided supervision and methodology; Li XH was responsible for conceptualization and supervision. Chong YT and Li XH share co-corresponding authorship for this work. This reflects their integrated and equally vital leadership roles from the project's inception to its completion. Professor Li XH was responsible for the initial conceptualization and provided strategic supervision. Complementing this, Professor Chong YT designed the study's methodology and provided hands-on supervision, ensuring the rigorous execution of the research. Together, they co-supervised the research team and are jointly responsible for the manuscript's scientific integrity and for all correspondence; all authors have read and approved the final manuscript.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xin-Hua Li, Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China. lixinh8@mail.sysu.edu.cn
Received: April 1, 2025 Revised: May 16, 2025 Accepted: August 8, 2025 Published online: September 27, 2025 Processing time: 181 Days and 5.2 Hours
Abstract
Porphyria refers to a group of rare inherited metabolic disorders caused by enzymatic deficiencies in the heme biosynthesis pathway. These deficiencies lead to the pathological accumulation of neurotoxic porphyrin precursors, resulting in multisystem damage. Currently, there are no curative therapeutic interventions, and patients frequently experience severe morbidity or life-threatening complications. Among the most critical manifestations is protoporphyric liver disease, in which hepatotoxic porphyrins and their precursors drive progressive hepatic injury and cholestasis. Persistent elevation of these metabolites can lead to irreversible parenchymal damage, significantly affecting both quality of life and long-term prognosis. The clinical presentation of porphyria-associated liver injury is highly variable and often has an insidious onset. However, a subset of patients may experience rapid progression to acute liver failure or fulminant hepatic dysfunction. Diagnosis is based on clinical evaluation and is confirmed by genetic testing. Current treatment strategies are focused on symptom management while underlying disease mechanisms remain unaddressed, posing significant therapeutic challenges. This review summarizes the pathophysiology, clinical manifestations, and diagnostic approaches for porphyria-associated liver injury, highlighting emerging therapies with the potential to improve patient outcomes.
Core Tip: Porphyria-related liver injury, driven by toxic accumulation of heme biosynthesis intermediates, presents diagnostic challenges due to nonspecific symptoms and insidious progression. The "Two-Hit Model" (porphyrin-protein aggregation and oxidative stress) underpins hepatotoxicity, while protoporphyria-associated cholestasis, liver failure, and acute hepatic porphyria-linked hepatocellular carcinoma (HCC) further increase morbidity. Diagnosis follows a multistep process integrating biochemical profiling, histopathological examination, and genetic testing. Current therapies are palliative, whereas emerging approaches—such as RNA interference (givosiran), melanocortin agonists (afamelanotide), and gene-editing technologies—provide mechanistic targeting. Early surveillance for HCC and multidisciplinary management are essential to mitigate life-threatening complications in these rare metabolic disorders.
