Neurofilament Light Chains in Serum Predict Post—Transjugular Intrahepatic Portosystemic Shunt Hepatic Encephalopathy

Abstract

Hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) insertion constitutes a frequent and severe complication. However, there is a lack of robust predictive biomarkers for post-TIPS HE, so far. This study evaluated the usefulness of neurofilament light chains (NfL) and glial fibrillary acidic protein (GFAP) in serum for predicting post-TIPS HE. Around 144 patients with cirrhosis from three centers were prospectively included and monitored for the occurrence of post-TIPS overt HE, liver transplantation, and death. Serum NfL and GFAP were evaluated before TIPS insertion using the single molecule array technology. In a subgroup of patients sequential NfL and GFAP levels were assessed at 30- and 180-days post-TIPS. While higher NfL levels (sHR 1.01, p = 0.036) were independently associated with post-TIPS OHE after adjusting for other risk factors, GFAP levels had no predictive ability. Consistently, only elevated NfL levels were associated with a higher risk of death/liver transplantation in multivariable analyses. Sequential measurements of NfL at 30 and 180 days after TIPS revealed that NfL levels remain constant until Day 30 followed by a decrease at day 180. Notably, GFAP levels did not change over time. Thus, NfL could be a valuable biomarker for identifying high-risk patients for post-TIPS HE.

Keywords

axonal damage / biomarkers / cognitive dysfunction / hepatic encephalopathy / post-TIPS HE / transjugular intrahepatic portosystemic shunt

References

[1] E. B. Tapper and N. D. Parikh, “Diagnosis and Management of Cirrhosis and Its Complications: A Review,” Jama 329, no. 18 (2023): 1589-1602.

[2] J. C. Garcia-Pagan, S. Saffo, M. Mandorfer, and G. Garcia-Tsao, “Where Does TIPS Fit in the Management of Patients With Cirrhosis?,” JHEP Reports 2, no. 4 (2020): 100122.

[3] H. Larrue, G. D'Amico, and P. Olivas, “TIPS Prevents Further Decompensation and Improves Survival in Patients With Cirrhosis and Portal Hypertension in an Individual Patient Data Meta-Analysis,” Journal of Hepatology 79, no. 3 (2023): 692-703.

[4] S. J. Gairing, L. Muller, R. Kloeckner, P. R. Galle, and C. Labenz, “Review Article: Post-TIPSS Hepatic Encephalopathy-current Knowledge and Future Perspectives,” Alimentary Pharmacology & Therapeutics 55, no. 10 (2022): 1265-1276.

[5] European Association for the Study of the Liver, “Electronic Address Eee, European Association for the Study of the L. EASL Clinical Practice Guidelines on Acute-on-Chronic Liver Failure,” Journal of Hepatology 79, no. 2 (2023): 461-491.

[6] C. Bureau, D. Thabut, C. Jezequel, et al., “The Use of Rifaximin in the Prevention of Overt Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt: A Randomized Controlled Trial,” Annals of Internal Medicine 174, no. 5 (2021): 633-640.

[7] Y. Li, Y. Guo, X. Wang, and L. Gao, “Association Between Sarcopenia and Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt in Patients With Cirrhosis: A Systematic Review and Meta-Analysis,” Abdominal Radiology 49, no. 2 (2024): 575-585.

[8] Y. Yang, S. Fu, B. Cao, et al., “Prediction of Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt Treatment: A Cohort Study,” Hepatology International 15, no. 3 (2021): 730-740.

[9] C. Labenz, M. Nagel, P. Kamper, et al., “Association Between Serum Levels of Neurofilament Light Chains and Minimal Hepatic Encephalopathy in Patients with Liver Cirrhosis,” Clinical and Translational Gastroenterology 12, no. 10 (2021): e00419.

[10] S. J. Gairing, S. Danneberg, L. Kaps, et al., “Elevated Serum Levels of Glial Fibrillary Acidic Protein Are Associated With Covert Hepatic Encephalopathy in Patients With Cirrhosis,” JHEP Reports 5, no. 4 (2023): 100671.

[11] A. Fiorillo, J. J. Gallego, F. Casanova-Ferrer, et al., “Neurofilament Light Chain Protein in Plasma and Extracellular Vesicles Is Associated With Minimal Hepatic Encephalopathy and Responses to Rifaximin Treatment in Cirrhotic Patients,” International Journal of Molecular Sciences 24, no. 19 (2023): 14727.

[12] K. de Wit, D. J. van Doorn, B. Mol, et al., “Neurofilament Light Chain but Not Glial Fibrillary Acidic Protein Is a Potential Biomarker of Overt Hepatic Encephalopathy in Patients With Cirrhosis,” Annals of Hepatology 29, no. 3 (2024): 101496.

[13] Y. Wang, Y. F. Xue, Y. F. Xu, M. W. Wang, J. Guan, and X. Chen, “Elevated Serum Neurofilament Light Chain Levels Are Associated With Hepatic Encephalopathy in Patients With Cirrhosis,” Metabolic Brain Disease 39, no. 6 (2024): 1099-1108.

[14] A. Tiede, L. Stockhoff, Z. Liu, et al., “TIPS Insertion Leads to Sustained Reversal of Systemic Inflammation in Patients With Decompensated Liver Cirrhosis,” Clinical and Molecular Hepatology 31, no. 1 (2025): 240-255.

[15] K. N. Varhaug, O. Torkildsen, K. M. Myhr, and C. A. Vedeler, “Neurofilament Light Chain as a Biomarker in Multiple Sclerosis,” Frontiers in Neurology 10 (2019): 338.

[16] S. Bittner, F. Steffen, T. Uphaus, et al., “Clinical Implications of Serum Neurofilament in Newly Diagnosed MS Patients: A Longitudinal Multicentre Cohort Study,” EBioMedicine 56 (2020): 102807.

[17] S. Engel, M. Protopapa, F. Steffen, et al., “Implications of Extreme Serum Neurofilament Light Chain Levels for the Management of Patients With Relapsing Multiple Sclerosis,” Therapeutic Advances in Neurological Disorders 14 (2021): 17562864211001977.

[18] M. C. Huang, H. Y. Tu, R. H. Chung, et al., “Changes of Neurofilament Light Chain in Patients With Alcohol Dependence Following Withdrawal and the Genetic Effect From ALDH2 Polymorphism,” European Archives of Psychiatry and Clinical Neuroscience 274, no. 2 (2024): 423-432.

[19] A. F. Ehrenbauer, H. Schneider, L. Stockhoff, et al., “Predicting Overt Hepatic Encephalopathy After TIPS: Value of Three Minimal Hepatic Encephalopathy Tests,” JHEP Reports 5, no. 9 (2023): 100829.

[20] R. de Franchis, J. Bosch, G. Garcia-Tsao, T. Reiberger, C. Ripoll, and V. Baveno, “Baveno VII—Renewing Consensus in Portal Hypertension,” Journal of Hepatology 76, no. 4 (2022): 959-974.

[21] K. Weissenborn, J. C. Ennen, H. Schomerus, N. Ruckert, and H. Hecker, “Neuropsychological Characterization of Hepatic Encephalopathy,” Journal of Hepatology 34, no. 5 (2001): 768-773.

[22] A. F. Ehrenbauer, J. F. M. Egge, M. M. Gabriel, et al., “Comparison of 6 Tests for Diagnosing Minimal Hepatic Encephalopathy and Predicting Clinical Outcome: A Prospective, Observational Study,” Hepatology 80, no. 2 (2024): 389-402.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.