Letter to the Editor: Serum alpha-fetoprotein dynamics in liver failure - prognostic implications and clinical insights

Multiple regimens of immune checkpoint inhibitors (ICIs) plus targeted therapies are commonly prescribed as first-line treatments for unresectable hepatocellular carcinoma (uHCC). Here, we aimed to investigate the correlation between dynamic changes of neutrophil-to-lymphocyte ratio (NLR) and tumor response to the combination of ICIs and targeted therapies for uHCC. Sixty-one patients who received ICIs plus targeted therapies for uHCC were enrolled in this retrospective study. The NLR before and at 3-6 weeks after treatments were assessed to calculate the dynamic NLR changes (ΔNLR). Multivariate logistic regression and Cox regression models were used to explore the relationship between dynamic NLR changes and tumor response or progression-free survival (PFS), respectively. Furthermore, we assessed the predictive effect of alpha-fetoprotein (AFP) changes in combination with dynamic NLR changes compared to AFP changes alone. The NLR at 3-6 weeks and ΔNLR after treatments significantly increased in patients who underwent progressive disease (PD), while the baseline NLR showed no significant difference between different tumor responses. Increased NLR and AFP after treatments were both independent predictors of PD (For NLR increase: OR, 2.28; 95% CI, 1.47-3.88, P < 0.001; For AFP increase: OR, 1.46; 95% CI, 1.03-2.17, P = 0.043), and correlated with worse PFS (for NLR increase: HR, 4.08; 95% CI, 1.99-8.36, P < 0.001; for AFP increase: HR, 2.10; 95% CI, 1.04-4.24, P = 0.039). The receiver operating characteristic (ROC) curve and net reclassification index (NRI) showed that the combination of dynamic NLR and AFP changes was better than AFP changes alone on predicting PD (AUC: 0.83 vs 0.68, P = 0.034; NRI: 0.340, P = 0.048) and PFS (AUC: 0.80 vs 0.70, P = 0.166; NRI: 0.431, P = 0.042). Dynamic changes of NLR might be an effective predictor of the therapeutic response to ICIs plus targeted therapies for uHCC.

Objective: To investigate the efficacy and diagnostic accuracy of changes in cytokine levels before and after non-biological artificial liver (referred to as ABL) treatment in patients with acute-on-chronic liver failure (ACLF) in order to establish a basis for treatment timing selection and short-term (28d) prognosis. Methods: 90 cases diagnosed with ACLF were selected and divided into a group receiving artificial liver treatment (45 cases) and a group not receiving artificial liver treatment (45 cases). Age, gender, first routine blood test after admission, liver and kidney function, and procalcitonin (PCT) of the two groups were collected. The 28-day survival of the two groups was followed-up for survival analysis. The 45 cases who received artificial liver therapy were further divided into an improvement group and a deterioration group according to the clinical manifestations before discharge and the last laboratory examination results as the efficacy evaluation indicators. Routine blood test, coagulation function, liver and kidney function, PCT, alpha fetoprotein (AFP), β-defensin-1 (HBD-1), 12 cytokines and other indicators were analyzed and compared. A receiver operating characteristic curve (ROC curve) was used to analyze the diagnostic efficacy of the short-term (28 d) prognosis and an independent risk factors affecting the prognosis of ACLF patients. According to different data, Kaplan-Meier method, log-rant test, t-test, Mann-Whitney U test, Wilcoxon rank-sum test, χ2 test, Spearman rank correlation analysis and logistic regression analysis were used for statistical analysis. Results: The 28-day survival rate was significantly higher in ACLF patients who received artificial liver therapy than that of those who did not receive artificial liver therapy (82.2% vs. 61.0%, P<0.05). The levels of serum HBD-1, alpha interferon (IFN-α) and interleukin-5 (IL-5) after artificial liver treatment were significantly lower in ACLF patients than those before treatment (P<0.05), while liver and coagulation function were significantly improved compared with those before treatment (P<0.05), and there was no statistically significant difference in other serological indexes before and after treatment (P＞0.05). Before artificial liver treatment, serum HBD-1 and INF-α levels were significantly lower in the ACLF improvement group than in the deterioration group (P<0.05) and were positively correlated with the patients' prognosis (deteriorating) (r=0.591, 0.427, P<0.001, 0.008). The level of AFP was significantly higher in the improved ACLF group than that in the deterioration group (P<0.05), and was negatively correlated with the prognosis (deteriorating) of the patients (r=-0.557, P<0.001). Univariate logistic regression analysis showed that HBD-1, IFN-α and AFP were independent risk factors for the prognosis of ACLF patients (P=0.001, 0.043, and 0.036, respectively), and that higher HBD-1 and IFN-α levels were associated with lower AFP level and a deteriorating prognosis. The area under the curve (AUC) of HBD-1, IFN-α, and AFP for short-term (28d) prognostic and diagnostic efficacy of ACLF patients was 0.883, 0.763, and 0.843, respectively, and the sensitivity and specificty was 0.75, 0.75, and 0.72, and 0.84, 0.80, and 0.83, respectively. The combination of HBD-1 and AFP had further improved the diagnostic efficiency of short-term prognosis of ACLF patients (AUC=0.960, sensitivity and specificity: 0.909 and 0.880 respectively). The combination of HBD-1+IFN-α+AFP had the highest diagnostic performance, with an AUC of 0.989, sensitivity of 0.900, and specificity of 0.947. Conclusion: Artificial liver therapy can effectively improve the clinical symptoms and liver and coagulation function of patients with ACLF; remove cytokines such as HBD-1, IFN-α, and IL-5 in patients with liver failure; delay or reverse the progression of the disease; and improve the survival rate of patients. HBD-1, IFN-α, and AFP are independent risk factors affecting the prognosis of ACLF patients, which can be used as biological indicators for evaluating the short-term prognosis of ACLF patients. The higher the level of HBD-1 and/or IFN-α, the higher the risk of disease deterioration. Therefore, artificial liver therapy should be started as soon as possible after the exclusion of infection. In diagnosing the prognosis of ACLF, HBD-1 has higher sensitivity and specificity than IFN-α and AFP, and its diagnostic efficiency is greatest when combined with IFN-α and AFP.

Objective: To investigate the predictive value and clinical significance of alpha-fetoprotein (AFP) levels in the prognosis of patients with liver failure treated with artificial liver plasma exchange (PE). Methods: A retrospective analysis was conducted on the clinical data of 96 liver failure patients. All patients underwent artificial liver plasma exchange therapy in addition to internal medicine treatments. Based on AFP test results, patients were divided into a low-AFP group (AFP &lt; 100 ng/mL, n = 32), a medium-AFP group (100 ≤ AFP &lt; 200 ng/mL, n = 32), and a high-AFP group (AFP ≥ 200 ng/mL, n = 32). Serum AFP levels were measured before artificial liver therapy (2nd day of admission), and on the 1st, 10th, and 20th day after therapy, as well as the final day (before discharge or end of life), to observe their variations. Results: Among the 96 patients, there were 4 cases (4.2%) of acute liver failure (ALF), 7 cases (7.3%) of subacute liver failure (SALF), 57 cases (59.4%) of acute-on-chronic liver failure (ACLF), and 28 cases (29.2%) of chronic liver failure (CLF), with an overall survival rate of 82.3% (79/96). The survival rate in the AFP &lt; 100 ng/mL group was lower than in the other two groups, and the survival rate increased progressively with rising AFP levels (P &lt; 0.05). Conclusion: Serum AFP levels are closely related to the efficacy of artificial liver plasma exchange therapy in liver failure patients. Monitoring the dynamic changes in AFP levels can help assess disease progression.

China is a big country with liver diseases, and various hepatitis viruses, drug poisons, and alcohol can cause liver injury and even liver failure. The key to the prognosis of patients with liver failure is liver self-repair and regeneration. Alpha-fetoprotein (AFP) has been extensively studied as a tumor marker in liver cancer, but its role in liver regeneration in patients with liver failure awaits further studies. This article summarizes the basic research on AFP in liver regeneration and the clinical research on AFP in acute liver failure and acute-on-chronic liver failure (ACLF), as well as the previous research findings of our group that AFP is an important prognostic index and regeneration factor for liver regeneration after hepatitis B virus-related ACLF. The analysis shows that further studies on the role of AFP in the prognosis of various types of liver failure and the mechanism of liver regeneration will help deepen our understanding of AFP and liver regeneration, thereby providing new ideas and methods for the clinical diagnosis, treatment, and prognostic evaluation of patients with various types of liver failure.

Failure of Fibrotic Liver Regeneration in Mice Is Linked to a Severe Fibrogenic Response Driven by Hepatic Progenitor Cell Activation

Objective: To investigate the value of alpha-fetoprotein (AFP) level on survived hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients treated with artificial liver. Methods: Clinical indicators of HBV-ACLF patients who were previously treated with plasma exchange-based artificial liver at our department were retrospectively collected. The difference of serum AFP level between the survival and the death group was compared at 30, 90 and 180 days after artificial liver treatment. The ROC curves of the subjects were plotted, and the sensitivity and specificity of AFP for the survival prediction of the patients at 30, 90 and 180 days after artificial liver surgery were calculated. AFP was divided into a high AFP group and a low AFP group using median value. AFP and postoperative survival predictive value at 30, 90, and 180 days were analyzed. Results: A total of 93 cases were included in this study. The AFP of the survival group at 30, 90, and 180 days was (231.0 ± 286.2) ng / ml, (237.69 ± 297) ng / ml, (229.44 ± 286.46) ng/ml, and the death group was (76.4 ± 104.7) ng/ml, (103.13 ± 116.99) ng / ml, (136.34 ± 2.9.29) ng/ml, respectively. AFP of the death group was significantly lower than the corresponding survival group (P < 0.05). Receiver operating characteristic (ROC) curve analyses indicated that the area under the curve (AUC) and its 95% confidence interval at 30, 90, and 180 days after artificial liver surgery were 0.739 (0.611 ~ 0.867), 0.675 (0.550 ~ 0.80), 0.653 (0.524 ~ 0.781), respectively. The median serum AFP value was 110 ng/ml, and the survival analysis showed that the survival time of the high AFP group was significantly higher than the low AFP group at 30 d (P = 0.01), 90 d (P = 0.04) and 180 d (P = 0.03) after artificial liver surgery. Conclusion: Serum AFP can be used as a predictor of survival for HBV-ACLF patients after artificial liver therapy and its clinical value needs to be further verified by the larger sample size.

We conducted a prospective study to evaluate the significance of simultaneous measurement of 3 currently used tumor markers in the evaluation of tumor progression and prognosis of patients with hepatocellular carcinoma (HCC). Three tumor markers for HCC, alpha-fetoprotein (AFP), Lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP), were measured in the same serum samples obtained from 685 patients at the time of initial diagnosis of HCC. Positivity for AFP >20 ng/dL, AFP-L3 >10% of total AFP, and/or DCP >40 mAU/mL was determined. In addition, tumor markers were measured after treatment of HCC. Of the 685 patients, 337 (55.8%) were positive for AFP, 206 (34.1%) were positive for AFP-L3, and 371 (54.2%) were positive for DCP. In a comparison of patients positive for only 1 tumor marker, patients positive for AFP-L3 alone had a greater number of tumors, whereas patients positive for DCP alone had larger tumors and a higher prevalence of portal vein invasion. When patients were compared according to the number of tumor markers present, the number of markers present clearly reflected the extent of HCC and patient outcomes. The number of markers present significantly decreased after treatment. Tumor markers AFP-L3 and DCP appear to represent different features of tumor progression in patients with HCC. The number of tumor markers present could be useful for the evaluation of tumor progression, prediction of patient outcome, and treatment efficacy.

Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury

BACKGROUNDLiver failure, particularly acute-on-chronic liver failure, is associated with high mortality (50%-90%). The plasma exchange (PE) mode of the artificial liver support system has been shown to improve clinical outcomes, although its efficacy may vary depending on the regenerative capacity of the liver. Alpha-fetoprotein (AFP), an oncofetal glycoprotein, is reactivated during liver regeneration and may serve as a prognostic biomarker. Previous studies have reported significantly higher post-PE AFP levels in survivors than in non-survivors (286.5 ng/mL vs 82.3 ng/mL at day 7). However, the predictive value of baseline AFP stratification and serial AFP kinetics during PE therapy remains unestablished. This study investigated whether serial AFP measurements predict clinical outcomes in liver failure patients receiving PE.AIMTo evaluate the predictive value of serial AFP measurements in liver failure patients receiving PE.METHODSThis retrospective study included 194 liver failure patients with complete AFP data, excluding those with tumors, bleeding disorders, allergies, or unstable conditions. Patients were stratified by baseline AFP into low-AFP (< 100 ng/mL, n = 60), medium-AFP (100-200 ng/mL, n = 70), and high-AFP (> 200 ng/mL, n = 64) groups. AFP was measured before PE and on days 1, 10, 20, and 25.RESULTSStratification by baseline AFP revealed significant gradients. The high-AFP group required fewer PE sessions than the low-AFP group (2.8 ± 1.0 vs 4.2 ± 1.5) but exhibited greater post-PE AFP elevation (75.1 ± 20.3 ng/mL vs 33.1 ± 10.2 ng/mL; P < 0.001). The high-AFP group demonstrated optimal values, including the lowest ammonia, bilirubin, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, and the highest albumin and prothrombin activity (all post hoc P < 0.05 vs low-AFP). The medium-AFP group showed intermediate values except for prothrombin activity (35.2% ± 8.6%), which was significantly lower than in both other groups (P < 0.001). The high-AFP group had a reduced incidence of spontaneous bacterial peritonitis (9.4% vs 25.0%; P = 0.003), superior three-month survival (90.6% vs 56.7%; P < 0.001), and a higher post-treatment three-month receiver operating characteristic area under the curve (0.8851 vs 0.7051).CONCLUSIONAFP dynamics correlate with regenerative capacity and clinical outcomes in liver failure. Serial AFP monitoring may enhance risk stratification and support personalized therapeutic strategies.

Norman Kneteman, Tito Livraghi, David Madoff, Eduardo de Santibanez, and Michael Kew Division of Transplantation, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada; Department of Interventional Radiology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; Division of Interventional Radiology, New York-Presbyterian/Weill Cornell Medical Center, New York, NY; General Surgery and Liver Transplant Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; and Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa

Alpha fetoprotein changes predict hepatocellular carcinoma survival beyond the Milan criteria after hepatectomy

Serum alpha-fetoprotein (AFP) is an important clinical indicator for screening, diagnosis, and prognosis of primary hepatocellular carcinoma (HCC). Our team's previous study showed that patients with negative AFP at baseline and positive AFP at relapse had a worse prognosis (N-P). Therefore, the aim of our study was to develop and validate a nomogram for this group of patients. A total of 513 patients with HCC who received locoregional treatments at Beijing You'an Hospital, Capital Medical University, from January 2012 to December 2019 were prospectively enrolled. Patients admitted from 2012 to 2015 were assigned to the training cohort (n = 335), while 2016 to 2019 were in the validation cohort (n =183). The clinical and pathological features of patients were collected, and independent risk factors were identified using univariate and multivariate Cox regression analysis as a basis for developing a nomogram. The performance of the nomogram was evaluated by C-index, receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) curves in the training and validation cohorts. The content of the nomogram includes gender, tumor number, tumor size, lymphocyte, direct bilirubin (DBIL), gamma-glutamyl transferase (GGT), and prealbumin. The C-index (0.717 and 0.752) and 1-, 3-, and 5-year AUCs (0.721, 0.825, 0.845, and 0.740, 0.868, 0.837) of the training and validation cohorts proved the good predictive performance of the nomogram. Calibration curves and DCA curves suggested accuracy and net clinical benefit rates. The nomogram enabled to classify of patients with dynamic changes in AFP into three groups according to the risk of recurrence: low risk, intermediate risk, and high risk. There was a statistically significant difference in RFS between the three groups in the training and validation cohorts (P<0.001). The nomogram developed and validated in this study had good predictive power for patients with dynamic changes in AFP.

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

AIMTo investigate predictive and prognostic value of serum alpha-fetoprotein (AFP) level and its dynamic changes in patients with advanced gastric cancer with elevated serum AFP (AFPAGC).METHODSOne hundred and five patients with AFPAGC were enrolled in the study, and all of them underwent at least one cycle of systemic chemotherapy at our institute and had serum AFP ≥ 20 ng/mL at diagnosis or recurrence. Clinicopathologic features, serum AFP level at diagnosis and changes during treatment, first-line chemotherapy regimens, efficacy and toxicity, and survival information were collected. A Person’s χ2 or Fisher’s exact test was used to measure the differences between variables. Survival prognostic factors were investigated using the Kaplan-Meier method and Cox regression.RESULTSMedian serum AFP level was 161.7 ng/mL (range, 22.9-2557110 ng/mL). Objective response rates (ORR) was significantly lower in the AFP ≥ 160 ng/mL group than in the AFP < 160 ng/mL group (30.4% vs 68.3%, P < 0.001). ORR to doublet regimens was significantly lower in the AFP ≥ 160 ng/mL group, whereas ORR to triplet regimens was similar between the two groups. Liver metastasis rate was significantly higher in the AFP ≥ 160 ng/mL group than in the AFP < 160 ng/mL (69.8% vs 50.0%, P < 0.001). Overall survival (OS) in the two cohorts did not show any significant difference (P = 0.712). Dynamic changes of AFP were consistent with response to chemotherapy, and median OS of patients with a serum AFP decline ≥ 50% and those with a serum AFP decline < 50% was 17.5 m and 10.0 m, respectively (P = 0.003). Hepatic (P = 0.005), peritoneal (P < 0.001), non-regional lymph node metastasis (P < 0.001), and portal vein tumor thrombus (PVTT) (P = 0.042) were identified as independent prognostic factors for AFPAGC.CONCLUSIONReal-time examination of AFP has great predictive and prognostic value for managing AFPAGC. For those with markedly elevated AFP, triplet regimens may be a better choice.

Sinusoidal Endothelial Cells Coordinate Liver Regeneration and Angiogenesis via Angiopoietin-2: An Ode to Prometheus