Lysyl oxidase-like 2 (LOXL2) Emerges as a Predictor of Liver Cancer Risk in HCV Patients After Successful Treatment

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Research indicates serum LOXL2 levels could serve as a predictor for hepatocellular carcinoma (HCC) risk in HCV patients who have achieved sustained virological response (SVR).

Hepatitis C virus cells circulating the human liver. liver cancer hcc Lysyl oxidase-like 2 LOXL2

Hepatitis C virus cells circulating the human liver.

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LOXL2 connects collagen fibers outside of cells and reflects changes in liver fibrosis. Serum LOXL2 levels were found to anticipate the onset of HCC following SVR in HCV-infected patients. Combining LOXL2 levels with alpha-fetoprotein (AFP) levels improves the accuracy of assessing the risk of HCC development after SVR. This implies that monitoring LOXL2 and AFP levels could aid in identifying patients at a higher risk of liver cancer, facilitating an enhanced surveillance strategy for early detection.

After achieving SVR, the median LOXL2 levels significantly decreased from 2.33 ng/mL before treatment to 1.31 ng/mL after treatment (p < 0.001). Post-treatment LOXL2 levels and other factors like fibrosis-4 index, platelet counts, specific protein levels, and AFP levels, were identified as independent predictive factors for developing HCC after SVR in the univariate analysis. Patients with higher post-treatment LOXL2 levels (≥ 2.08 ng/mL) and AFP levels (≥ 5.0 ng/mL) had a significantly higher incidence of HCC development after SVR compared to patients with lower levels of these markers.

3 Key Takeaways

  1. Serum LOXL2 levels may predict HCC risk in HCV patients post-SVR, aiding in risk assessment alongside AFP levels.
  2. Following SVR, LOXL2 levels significantly decrease, reflecting inflammation resolution and potentially indicating reduced HCC risk.
  3. Combining LOXL2 and AFP levels could enhance surveillance for early HCC detection post-SVR, improving patient outcomes.

“Given that liver fibrosis is one of the significant factors in post-SVR HCC development, various markers that reflect the severity of fibrosis, such as the FIB-4 index, WFA+‐M2BP levels, and platelet counts, have been extensively investigated and reported as predictors,” according to the investigators. “Degradation of the deposited fibers in the ECM occurs in patients who have achieved SVR following DAA therapy.”

This was a retrospective study that analyzed data from 137 with chronic HCV infection who had not developed HCC and had attained SVR through direct-acting antiviral therapy. The study measured LOXL2 levels in the patient's blood before and after treatment. Other factors analyzed included the fibrosis-4 index, platelet counts, levels of specific proteins related to liver damage, and AFP levels.

“In our initial investigation, we characterized the serum LOXL2 levels as a clinical marker. The concentration of serum LOXL2 was elevated in patients infected with HCV compared to that in healthy individuals, and it rapidly decreased following HCV clearance, suggesting a parallel with the resolution of inflammation,” according to the investigators. “This pattern was also observed for the FIB-4 index and WFA+-M2BP levels, which decreased significantly after SVR was achieved. LOXL2 is induced via various pathways.”

This study has limitations, including the absence of a validation cohort to confirm results and the inability of the proposed system to identify individuals at zero risk of developing post-SVR HCC. The retrospective design and potential selection bias should be considered. The study confirmed diabetes mellitus as an independent risk factor alongside serum LOXL2 levels, but the small number of patients with both factors limits evaluation. Metabolic factors in predicting post-SVR HCC development require further exploration. The cohort's biases, such as genotype 1 restriction and a higher proportion of advanced fibrosis cases, may contribute to the increased incidence of HCC development post-SVR compared to recent reports.

“Notably, the promoter region of LOXL2 contains the SMAD binding sequence, indicating that LOXL2 expression increases in parallel with virus-induced inflammation and subsequent TGF-β expression,” according to the investigators. “LOXL2 expression is also triggered by the hypoxia/hypoxia-inducible factor-1 (HIF-1) pathway, or by ECM stiffness followed by the activation of integrins, c-Jun N-terminal kinase (JNK)/c-Jun, or MEK1/2-ERK1/2.”

In summary, serum LOXL2 levels could forecast HCC in HCV patients post-SVR. Monitoring LOXL2 and AFP levels aids in risk assessment. LOXL2 decreases post-SVR, correlating with inflammation resolution. Limitations include a lack of validation cohort and potential bias. Further exploration of metabolic factors is needed. LOXL2 reflects virus-induced inflammation and fibrosis progression.

Reference
Chida T, Ohta K, Noritake H, et al.Lysyl oxidase-like 2 as a predictor of hepatocellular carcinoma in patients with hepatitis C virus after sustained virological response. Sci Rep. Published May 13, 2024. Accessed May 16, 2024. doi: https://doi.org/10.1038/s41598-024-61366-y
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