Duan RX, Liu L, Wang Y, Wu WM. Prognostic value of combined detection of alpha-fetoprotein, plasma prothrombin activity, and serum prealbumin in acute-on-chronic liver failure. World J Gastrointest Surg 2025; 17(2): 99531 [DOI: 10.4240/wjgs.v17.i2.99531]
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/
Rui-Xian Duan, Yan Wang, Department of Infectious Diseases, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, Shanxi Province, China
Ling Liu, Department of Pulmonary Diseases, Shanxi Provincial Integrated TCM and WM Hospital, Taiyuan 030013, Shanxi Province, China
Author contributions: Duan RX performed the study, designed the research and wrote the manuscript; Duan RX, Liu L, Wang Y, and Wu WM analyzed the data; and all authors have read and approve the final manuscript.
Institutional review board statement: This study was approved by the Ethic Committee of Shanxi Bethune Hospital.
Informed consent statement: The requirement for written informed consent was waived due to retrospective design of the study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Dataset available from the corresponding author at wu.wenming1007@163.com.
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/
Received: October 11, 2024 Revised: November 11, 2024 Accepted: December 19, 2024 Published online: February 27, 2025 Processing time: 103 Days and 0.9 Hours
Abstract
BACKGROUND
Acute-on-chronic liver failure (ACLF) is a liver disease based on chronic liver disease, which is significantly influenced by clinical treatment regimen and disease status, and despite the existence of multiple prognostic assessment indicators for ACLF, the overall sensitivity and accuracy are relatively low.
AIM
To investigate the prognostic value of the combined detection of alpha-fetoprotein (AFP), plasma prothrombin activity (PTA), and serum prealbumin (PA) in ACLF.
METHODS
This retrospective study included 87 patients with ACLF admitted from February 2021 to February 2023 and categorized them into the survival (n = 47) and death (n = 40) groups according to their clinical outcomes 3 months posttreatment. All the participants underwent AFP, PTA, and PA level measurements upon admission. Baseline data, as well as AFP, PTA, and PA levels, were comparatively analyzed. Pearson correlation coefficients were utilized to analyze the correlations of AFP, PTA, and PA with different survival outcomes in patients with ACLF. Receiver operating characteristic (ROC) curves and areas under the curves were used to evaluate the predictive value of AFP, PTA, and PA for ACLF prognosis.
RESULTS
AFP, PTA, and PA levels were markedly decreased in the death group than in the survival group (P < 0.05). Pearson analysis indicated a positive association of the AFP, PTA, and PA levels with the survival of patients with ACLF (P < 0.05). ROC curve analysis determined the sensitivity and specificity of the combined diagnosis at 91.24% and 100.00%, respectively, both of which were notably increased compared to the single-index diagnosis. The ROC of their combined diagnosis was 0.989, significantly surpassing 0.907, 0.849, and 0.853 of AFP, PTA, and PA, respectively. No statistically significant variance was determined in the sensitivity and specificity of the combined diagnosis vs the single detection (P > 0.05).
CONCLUSION
The combined detection of AFP, PTA, and PA levels demonstrates favorable diagnostic value for the short-term prognosis of patients with ACLF, featuring high sensitivity and specificity.
Core Tip: Acute-on-chronic liver failure (ACLF) is a type of chronic hepatopathy-based liver disease featuring severe acute liver function. They are significantly influenced by clinical treatment regimens and disease conditions, with relatively low overall sensitivity and accuracy, despite the presence of multiple prognostic assessment indicators for ACLF. This study aims to investigate the prognostic value of the combined detection of alpha-fetoprotein, plasma prothrombin activity, and serum prealbumin in ACLF.
Citation: Duan RX, Liu L, Wang Y, Wu WM. Prognostic value of combined detection of alpha-fetoprotein, plasma prothrombin activity, and serum prealbumin in acute-on-chronic liver failure. World J Gastrointest Surg 2025; 17(2): 99531
Liver failure is a liver disorder induced by multiple-factor interaction, causing severe impairment or decompensation of liver function, accompanied by symptoms, including jaundice, coagulation dysfunctions, hepatic encephalopathy, and ascites[1]. Acute-on-chronic liver failure (ACLF), as a type of chronic hepatopathy-based liver disease featuring severe acute liver function decompensation due to acute inducement, is a complex syndrome with high mortality caused by liver and extrahepatic organ injury and failure, with a short-term mortality rate as high as 50%-60%, which seriously threatens the life safety of patients[2,3]. ACLF exhibits complicated etiology and pathological mechanisms. At present, many studies believe that various hepatitis virus infections are the primary causes of ACLF, and bacterial infections, drugs, and immunosuppression are predominant factors[4]. ACLF is treated based on comprehensive therapies, such as anti-inflammatory and hepatoprotective measures, antiviral treatment, nutritional support, and symptomatic therapy, to mitigate the continuous damage to liver function due to harmful substances, alleviate the clinical symptoms of patients, and delay disease progression[5]. However, some evidence has indicated that many complications interact with each other during disease progression and treatment, which exacerbates liver cell deterioration, causing multiple organ damage, failure, and even death[6]. Therefore, an effective early warning and accurate assessment system is beneficial for clinicians to adjust treatment plans and optimize medical resource allocation, which controls the disease process and reduces the mortality rate to a certain extent.
Multiple prognostic assessment indicators for ACLF are significantly affected by clinical treatment regimens and disease conditions, with relatively low overall sensitivity and accuracy, despite their presence[7]. Quantitative alpha-fetoprotein (AFP) detection is a relatively favorable approach for evaluating hepatocyte regeneration and inferring liver failure prognosis. An increased AFP level indicates a favorable prognosis. Plasma prothrombin activity (PTA) sensitively and specifically reflects the extent of liver function impairment and plays a crucial role in ACLF diagnosis, treatment, and prognosis assessment. Serum prealbumin (PA), one of the proteins synthesized by the liver, is used to evaluate the degree of liver function injury, disease severity, prognosis, etc.[8-10]. Accurately assessing the degree of liver function injury and the prognosis of liver failure with a single laboratory indicator is challenging, considering the complex etiology and pathogenesis of ACLF, diverse complications, rapid disease progression, and various clinical intervention approaches, whereas the combined prediction of multiple indexes improves the accuracy and scientificity of disease prediction[11]. Hence, this article selected the clinical data of 87 patients with ACLF admitted at our hospital from February 2020 to February 2022, analyzed their AFP, PTA, and PA levels, and investigated the correlation between the aforementioned indicators and the prognosis of patients with ACLF to effectively assess the therapeutic effect and disease prognosis and, to a certain extent, guide clinicians to select the optimal treatment plan and improve the survival rate of patients. The report is presented as follows.
MATERIALS AND METHODS
General information
The retrospective research included 87 patients with ACLF admitted at Shanxi Bethune Hospital from February 2020 to February 2022 and categorized them into the survival (n = 47) and death groups (n = 40) based on their clinical outcomes 3 months posttreatment. The comparison of the general information, such as gender and age, between the two groups of patients revealed no marked differences (P > 0.05), indicating comparability. AFP, PTA, and PA levels were measured in all patients after admission. The hospital’s medical ethics committee approved this study.
Inclusion and exclusion criteria
Inclusion criteria were: (1) Meeting the diagnostic criteria for ACLF in the Guidelines for Diagnosis and Treatment of Liver Failure[12] formulated by Society of Infectious Diseases in 2018; (2) Confirmed as ACLF through laboratory indicators and imaging examinations; (3) Age of 18-75 years; (4) Disease course of > 6 months; and (5) Clear chronic liver diseases history.
Exclusion criteria were: (1) Severe dysfunction of the heart, lung, kidneys, and other important organs; (2) Severe diseases of the coagulation, respiratory, urinary, and endocrine systems; (3) Malignant tumors, such as liver malignancy, gastric cancer, testicular cancer, etc.; (4) Liver failure caused by alcoholic, drug, and autoimmune factors; (5) Systemic infectious diseases before admission; (6) Recent treatment with immunosuppressants, anticoagulants, and antiinfective drugs; and (7) Women during pregnancy and lactation.
Research methods
Treatment: The patient was instructed to rest in bed after admission. Improvements were performed in terms of energy, vitamin, and protein supplementation, as well as maintaining water-electrolyte balance and acid-base balance, and preventing complications. Additionally, liver-protecting drugs were administered according to the patient’s physical condition and disease status, including magnesium isoglycyrrhizinate (intravenous infusion of 200 mg, once daily) and ademetionine 1,4-butane-disulfonate (intravenous infusion of 1.0 g, once daily); hepatocyte growth-promoting factor at 120 mg through intravenous infusion once daily; blood products, such as human albumin, prothrombin complex, and plasma, along with artificial liver; oral nucleoside analogs and anti-hepatitis B virus treatment for hepatitis virus-infected patients. Additionally, the risks of bleeding and hepatic encephalopathy in patients were assessed timely, and antiinfective intervention was provided. Treatment effect criteria[13]: Improvement refers to a significant enhancement in clinical symptoms, vital signs, etc., a decrease of > 50% in total bilirubin level compared to the peak during treatment, an increase of > 40% in PTA level compared to the peak during treatment or within the normal range, and an albumin level of > 28 g/L. Ineffective indicates not meeting the above criteria.
Indicator detection methods: Fasting peripheral venous blood was collected from all patients in the early morning of the next day after admission for tests, including routine blood tests, coagulation function, biochemical tests, and AFP quantification. The serum AFP level was identified by radioimmunoassay, using kits provided by North Reagent Company. The prothrombin time was detected with electrochemiluminescence. The PTA level was calculated as follows: PTA = [control PT × (1 - 0.6)/patient PT × (1 - 0.6)] × 100%[14]. The PA level was detected with the Hitachi 7170A/AU2700 automatic biochemical analyzer, and Delta Med Biotech Co. Ltd provided the kit. All measurements were strictly performed following the operation manual of the kit.
Outcome measures
Outcome measures: (1) The baseline data of patients with ACLF with different survival outcomes, including gender, age, body mass index, disease course, and primary disease type, were compared; (2) AFP, PTA, and PA levels in patients with ACLF with different survival outcomes were compared; (3) Pearson correlation coefficients were utilized to analyze the correlations of AFP, PTA, and PA levels with different survival outcomes of patients with ACLF; and (4) The receiver operating characteristic (ROC) curves and areas under the curves (AUCs) were utilized to assess the diagnostic value of AFP + PTA + PA detection for the prognosis of patients with ACLF.
Statistical analysis
Data were imported into Statistical Package for the Social Sciences version 24.0 for statistical analysis. Normally distributed quantitative data were expressed as mean ± SD, and the t-test was utilized for comparison between groups. Enumeration data were expressed as the number of cases (n) and percentage (%), and the comparison between groups was conducted with the χ2 test. The correlations of AFP, PTA, and PA levels with different survival outcomes of patients with ACLF were analyzed with Pearson correlation coefficients. ROC curves and AUCs were utilized to assess the predictive value of AFP, PTA, and PA for ACLF prognosis. A P value of < 0.05 indicated a statistically significant difference.
RESULTS
Comparison of basic data
The results revealed no evident between-group differences in basic data in terms of sex, age, body mass index, disease course, and primary disease type (P > 0.05), indicating that the two groups were comparable (Table 1).
Table 1 Inter-group comparison of basic data, n (%).
Groups
Survival group (n = 47)
Death group (n = 40)
Statistical values
P value
Sex
4.315
0.092
Male
35 (74.47)
31 (77.50)
Female
12 (25.53)
9 (22.50)
Age (years old)
49.31 ± 10.29
50.32 ± 11.23
5.327
0.153
Body mass index (kg/m2)
22.94 ± 2.34
22.97 ± 2.50
4.142
0.325
Disease course (years)
9.21 ± 3.20
9.25 ± 3.32
5.424
0.619
Type of primary disease
4.527
0.153
Viral hepatitis
32 (68.09)
28 (70.00)
Alcoholic hepatitis
10 (21.28)
8 (20.00)
Drug-induced hepatitis
4 (8.51)
3 (7.50)
Others
1 (2.13)
1 (2.50)
Comparison of AFP, PTA, and PA levels in patients with ACLF with different survival outcomes
The survival group demonstrated notably lower AFP, PTA, and PA levels than the survival group (P < 0.05), indicating that patients in the death group had more severe liver damage (Table 2).
Table 2 Inter-group comparison of alpha-fetoprotein, prothrombin activity, and prealbumin levels among acute-on-chronic liver failure patients with different survival outcomes, mean ± SD.
Groups
Survival group (n = 47)
Death group (n = 40)
Statistical values
P value
AFP (ng/mL)
120.99 ± 11.81
77.65 ± 25.14
10.539
< 0.001
PTA (μg/L)
34.81 ± 8.11
25.84 ± 4.56
6.207
< 0.001
PA (mg/L)
85.08 ± 24.30
50.27 ± 22.18
6.930
< 0.001
Correlations of AFP, PTA, and PA with different survival outcomes of patients with ACLF
The Pearson analysis (Table 3) indicated that AFP (r = 0.753, P < 0.001), PTA (r = 0.559, P < 0.001), and PA (r = 0.601, P < 0.001) levels were positively correlated with survival of patients with ACLF.
Table 3 Correlations of alpha-fetoprotein, prothrombin activity, and prealbumin with different survival outcomes.
Groups
Survival outcomes (survival)
r
P value
AFP (ng/mL)
0.753
< 0.001
PTA (μg/L)
0.559
< 0.001
PA (mg/L)
0.601
< 0.001
Diagnostic value of combined detection of AFP, PTA, and PA levels for the prognosis of patients with ACLF
ROC curve analysis revealed that the sensitivity and specificity were 80.00% and 100.00% in AFP, 74.50% and 87.50% in PTA, and 70.20% and 95.50% in PA in diagnosing the prognosis of patients with ACLF, respectively. Their combined diagnosis exhibited a sensitivity of 95.70% and a specificity of 95.50% in diagnosing the prognosis of patients with ACLF, which is significantly higher than those of single-indicator diagnosis. The AUC of the combined diagnosis of the three was 0.989, which was significantly higher than the 0.907, 0.849, and 0.853 of AFP, PTA, and PA, respectively. The sensitivity and specificity of joint diagnosis demonstrated no statistically significant difference compared to the single detection (P > 0.05). The results indicate that the combined diagnosis of AFP, PTA, and PA improves the sensitivity and specificity of the prognostic diagnosis for patients with ACLF and better predicts the short-term survival conditions of such patients (Table 4 and Figure 1).
Figure 1 Receiver operating characteristic curves of the combined detection of alpha-fetoprotein, prothrombin activity and prealbumin levels for prognosis diagnosis of acute-on-chronic liver failure patients.
ROC: Receiver operating characteristic; AFP: Alpha-fetoprotein; PTA: Prothrombin activity; PA: Prealbumin.
Table 4 Diagnostic value of alpha-fetoprotein + prothrombin activity + prealbumin detection for prognosis of acute-on-chronic liver failure patients.
Indicators
Sensitivity (%)
Specificity (%)
Youden index
Cut-off
AUC
95%CI
AFP (ng/mL)
80.00
100.00
0.800
99.080
0.907
0.839-0.976
PTA (μg/L)
74.50
87.50
0.620
30.795
0.849
0.766-0.931
PA (mg/L)
70.20
95.50
0.652
78.235
0.853
0.773-0.933
Joint detection
95.70
95.50
0.907
-
0.989
0.974-1.000
DISCUSSION
ACLF, as a prevalent type of liver failure, has become the leading cause of death in patients with chronic liver diseases in China. Progressive liver function impairment due to the interaction of factors, such as inflammatory responses within the liver, immune dysfunction, and neutrophil dysfunction, may have caused ACLF. The early symptoms are not prominent, and the onset is acute. The disease rapidly progresses, with symptoms, including digestive tract symptoms, jaundice, coagulation dysfunction, and hepatic encephalopathy that gradually emerge, and even induce multiple organ failure and death[15]. Some scholars have emphasized a golden time window, characterized by excessive immune responses, from the onset and development of ACLF to liver failure[16]. The liver cell function of patients can be reversed if active and effective intervention measures are provided, thereby improving their outcomes and reducing mortality. At present, clear criteria for judging the efficacy of ACLF treatment at home and abroad are lacking. Objective detection indicators are often selected to reflect the dynamic changes of the disease, assess the severity of the patient’s condition, and predict the death risk of the patient after a treatment period[17]. Up to now, the markers used to evaluate ACLF prognosis include oxidative stress parameters, proteomics-related markers, inflammation-related indices, and immune response markers. However, these prognostic assessment systems all demonstrate certain advantages and disadvantages, and a unified and accurate prognostic assessment system remains lacking[18]. This study analyzed AFP, PTA, and PA levels in patients with ACLF and investigated their correlations with patient prognosis to provide a scientific basis for treatment regimen selection for the disease.
In recent years, the triple-hit hypothesis has been the most acknowledged pathogenesis of ACLF among clinical scholars. That is, several hepatocytes are induced to undergo necrosis and apoptosis under circumstances where various factors interact to cause immune system regulation disorders, microcirculation abnormalities, and endotoxin expression obstacles, thereby causing and intensifying liver failure. Hence, accurately grasping the degree of hepatocyte necrosis and the process of hepatocyte regeneration holds significant guiding value for assessing the prognosis of patients with ACLF. AFP, as one of the glycoproteins jointly synthesized and secreted by the liver and yolk sac during the fetal period, facilitates hepatocyte proliferation and growth. Its synthesis is inhibited and the level rapidly drops to a normal and low level after fetal birth. Some genes within the body are activated and AFP is rapidly synthesized when normal adults suffer from liver cell damage or carcinogenesis, causing a rapid increase in the AFP content within liver cells[19]. Some research has revealed the possible involvement of AFP in regulating hepatocyte proliferation[20]. The abnormally expressed AFP in liver failure may be because AFP activates the intracellular calcium ion concentration of liver cells, stimulates the activity of cell membrane receptors, increases cell membrane permeability, and improves the cAMP concentration, dephosphorylation, and the content of phosphorylated intracellular proteins, thereby promoting liver cell mitosis and activating hepatocyte regeneration function. The regeneration rate of hepatocytes predicts the prognosis of patients with ACLF to a certain extent. Huang et al[21] revealed that the AFP level of ACLF patients can, to a certain extent, reflect hepatocyte regeneration and indicate hepatocyte inflammatory and necrotic conditions. Additionally, the AFP level increases as the condition of patients with ACLF deteriorates, and a higher AFP level indicates a good prognosis. The liver performs vital physiological functions in vivo, including metabolism, excretion, and coagulation. Both liver cells and hepatic sinusoidal endothelial cells within the liver synthesize various coagulation factors and anticoagulant substances, thereby playing a crucial role in maintaining the balance of the coagulation-anticoagulant fibrinolysis system. The number of normal liver functional cells drops sharply and the synthesis of coagulation factors decreases when liver cells function abnormally, especially when they undergo necrosis and apoptosis. The plasma PTA level undergoes a significant decline in a short period considering the short half-life of coagulation factors. Thus, the body’s coagulation function can be effectively monitored by detecting the plasma PTA level, thereby indirectly reflecting the extent of liver injury[22]. Thus, the plasma PTA level can serve as an important indicator for evaluating the severity and prognosis of patients with ACLF, demonstrating high sensitivity. Serum PA is a plasma protein with a short biological half-life that is completely synthesized by the liver. Numerous previous studies have revealed that its level does not significantly fluctuate due to the effects of drugs[23]. However, serum PA demonstrates a significant reduction and can be rapidly detected in peripheral venous blood when liver cells are damaged. It has become a crucial indicator of hepatocyte synthesis and reserve functions and can sensitively reflect liver function damage, thereby holding a high diagnostic value for the prognosis assessment of liver failure[24]. The possible reasons for the decreased serum PA in patients with ACLF are as follows: Liver parenchymal function impairment and liver’s detoxification ability reduction, which increased the concentration of endogenous toxins and pathogenic factor-related cells in the body, thereby triggering metabolic disorders in liver cells and lowering serum PA levels. Additionally, serum PA effectively eliminates toxic substances produced by liver metabolism in the nonspecific immune function defense system of the liver, which intensifies PA consumption in the serum. Moreover, the insufficient nutritional support and energy supply in the body caused limited synthesis of serum PA, thereby causing a rapid decline in serum PA levels during liver injury[25]. Zhang et al[26] revealed that the serum PA level can serve as a specific and independent predictor of the 30-day treatment mortality rate in patients with hepatitis B virus-related ACLF and effectively evaluate patient short-term prognosis. The results of this study indicated that AFP, PTA, and PA levels were notably reduced in the deceased compared with ACLF survivors. Additionally, an inverse association of AFP, PTA, and PA levels with different survival outcomes of ACLF patients was determined by Pearson analysis. These are largely similar to the results of the aforementioned literature, indicating that AFP, PTA, and PA levels are closely associated with the prognosis of patients with ACLF and play a crucial role in patient outcome assessment.
ROC curves were plotted in this study, and the analysis results indicated that the combined diagnosis based on AFP, PTA, and PA levels demonstrated a sensitivity and a specificity of 91.24% and 100.00%, respectively, which were significantly higher than those of the single-index diagnosis. The AUC of the combined diagnosis of AFP, PTA, and PA was 0.926, which was significantly higher than that of AFP, PTA, and PA alone (0.905, 0.846, and 0.852, respectively). No statistically significant difference in the sensitivity and specificity were found between the combined diagnosis and the individual detection. It is similar to the research results, indicating that the combined diagnosis with AFP, PTA, and PA can improve the sensitivity and specificity of the prognosis diagnosis for patients with ACLF and better predict the short-term survival conditions of such patients.
This study has limitations. Firstly, no grouping analysis was conducted on the sensitivity and specificity of indicators for patients of different genders, ages, and genders due to the small number of cases. Second, this study only analyzed AFP, PTA, and PA levels in patients treated for 3 months, thereby lacking dynamic observation of AFP, PTA, and PA and prognostic analysis of patients at different levels. Third, only biochemical and laboratory indicators are involved, and no optimization research has been conducted according to different scoring systems. In the future, the sample size needs to be expanded, the experimental scheme be optimized, and prospective and multicenter research be conducted to predict the prognosis of patients with ACLF more accurately.
CONCLUSION
Altogether, the combined detection of AFP, PTA, and PA levels is of great value in assessing the prognosis of patients with ACLF. The combined diagnosis is conducive to comprehensively grasping the liver function and prognosis of patients with ACLF, thereby providing a reference for clinicians to formulate personalized treatment strategies and helping to prolong patient survival.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade C
Novelty: Grade B, Grade B
Creativity or Innovation: Grade C, Grade C
Scientific Significance: Grade B, Grade C
P-Reviewer: Korchagina EV; Pavlova I S-Editor: Wang JJ L-Editor: A P-Editor: Zhao S
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