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World Journal of Gastroenterology Jan 2022Alpha-fetoprotein (AFP) is an oncofetal glycoprotein that has been used as a tumor marker for hepatocellular carcinoma (HCC) in combination with ultrasound and other... (Review)
Review
Alpha-fetoprotein (AFP) is an oncofetal glycoprotein that has been used as a tumor marker for hepatocellular carcinoma (HCC) in combination with ultrasound and other imaging modalities. Its utility is limited because of both low sensitivity and specificity, and discrepancies among the different methods of measurements. Moreover, its accuracy varies according to patient characteristics and the AFP cut-off values used. Combination of AFP with novel biomarkers such as AFP-L3, Golgi specific membrane protein (GP73) and des-gamma-carboxyprothrombin significantly improved its accuracy in detecting HCC. Increased AFP level could also signify severity of hepatic destruction and subsequent regeneration and is commonly observed in patients with acute and chronic liver conditions and cirrhosis. Hereditary and other non-hepatic disorders can also cause AFP elevation.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Liver Cirrhosis; Liver Neoplasms; alpha-Fetoproteins
PubMed: 35110946
DOI: 10.3748/wjg.v28.i2.216 -
International Journal of Biological... 2022Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has been acknowledged as a leading cause of death among cirrhosis patients. Difficulties in... (Review)
Review
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has been acknowledged as a leading cause of death among cirrhosis patients. Difficulties in early diagnosis and heterogeneity are obstacles to effective treatment, especially for advanced HCC. Liver transplantation (LT) is considered the best therapy for HCC. Although many biomarkers are being proposed, alpha-fetoprotein (AFP), which was identified over 60 years ago, remains the most utilized. Recently, much hope has been placed in the immunogenicity of AFP to develop novel therapies, such as AFP vaccines and AFP-specific adoptive T-cell transfer (ACT). This review summarizes the performance of AFP as a biomarker for HCC diagnosis and prognosis, as well as its correlation with molecular classes. In addition, the role of AFP in LT is also described. Finally, we highlight the mechanism and application prospects of two immune therapies (AFP vaccine and ACT) for HCC. In general, our review points out the prevalence of AFP in HCC, accompanied by some controversies and novel directions for future research.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Immunotherapy; Liver Neoplasms; Liver Transplantation; alpha-Fetoproteins
PubMed: 35002508
DOI: 10.7150/ijbs.64537 -
Gastroenterology May 2018Society guidelines differ in their recommendations for surveillance to detect early-stage hepatocellular carcinoma (HCC) in patients with cirrhosis. We compared the... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Society guidelines differ in their recommendations for surveillance to detect early-stage hepatocellular carcinoma (HCC) in patients with cirrhosis. We compared the performance of surveillance imaging, with or without alpha fetoprotein (AFP), for early detection of HCC in patients with cirrhosis.
METHODS
Two reviewers searched MEDLINE and SCOPUS from January 1990 through August 2016 to identify published sensitivity and specificity of surveillance strategies for overall and early detection of HCC. Pooled estimates were calculated and compared using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis guidelines.
RESULTS
Thirty-two studies (comprising 13,367 patients) characterized sensitivity of imaging with or without AFP measurement for detection of HCC in patients with cirrhosis. Ultrasound detected any stage HCC with 84% sensitivity (95% confidence interval [CI] 76%-92%), but early-stage HCC with only 47% sensitivity (95% CI 33%-61%). In studies comparing ultrasound with vs without AFP measurement, ultrasound detected any stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (relative risk [RR] 0.88; 95% CI 0.83-0.93) and early-stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (RR 0.81; 95% CI 0.71-0.93). However, ultrasound alone detected HCC with a higher level of specificity than ultrasound plus AFP measurement (RR 1.08; 95% CI 1.05-1.09). Ultrasound with vs without AFP detected early-stage HCC with 63% sensitivity (95% CI 48%-75%) and 45% sensitivity (95% CI 30%-62%), respectively (P = .002). Only 4 studies evaluated computed tomography or magnetic resonance image-based surveillance, which detected HCC with 84% sensitivity (95% CI 70%-92%).
CONCLUSIONS
We found ultrasound alone has a low sensitivity to detect early stage HCC in patients with cirrhosis. Addition of AFP to ultrasound significantly increases sensitivity of early HCC detection in clinical practice.
Topics: Adult; Aged; Carcinoma, Hepatocellular; Early Detection of Cancer; Female; Humans; Liver Cirrhosis; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Sensitivity and Specificity; Tomography, X-Ray Computed; Ultrasonography; alpha-Fetoproteins
PubMed: 29425931
DOI: 10.1053/j.gastro.2018.01.064 -
Endocrine Regulations Jan 2023Diabetes mellitus is characterized by hyperglycemia and abnormalities in insulin secretion and function. This review article focuses on various liver parameters,... (Review)
Review
Diabetes mellitus is characterized by hyperglycemia and abnormalities in insulin secretion and function. This review article focuses on various liver parameters, including albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), alpha fetoprotein (AFP), alpha 1 antitrypsin (AAT), ammonia, bilirubin, bile acid, gamma-glutamyl transferase (GGT), immunoglobulin, lactate dehydrogenase (LDH), and total protein. These parameters play significant roles in the development of different types of diabetes such as type 1 diabetes (T1DM), type 2 diabetes (T2DM) and gestational diabetes (GDM). The article highlights that low albumin levels may indicate inflammation, while increased ALT and AST levels are associated with liver inflammation or injury, particularly in non-alcoholic fatty liver disease (NAFLD). Elevated ALP levels can be influenced by liver inflammation, biliary dysfunction, or bone metabolism changes. High bilirubin levels are independently linked to albuminuria in T1DM and an increased risk of T2DM. Elevated GGT levels are proposed as markers of oxidative stress and liver dysfunction in T2DM. In GDM, decreased serum AFP levels may indicate impaired embryo growth. Decreased AFP levels in T2DM can hinder the detection of hepatocellular carcinoma. Hyperammonemia can cause encephalopathy in diabetic ketoacidosis, and children with T1DM and attention deficit hyperactivity disorder often exhibit higher ammonia levels. T2DM disrupts the regulation of nitrogen-related metabolites, leading to increased blood ammonia levels. Bile acids affect glucose regulation by activating receptors on cell surfaces and nuclei, and changes in bile acid metabolism are observed in T2DM. Increased LDH activity reflects metabolic disturbances in glucose utilization and lactate production, contributing to diabetic complications. Poor glycemic management may be associated with elevated levels of IgA and IgG serum antibodies, and increased immunoglobulin levels are also associated with T2DM.
Topics: Child; Female; Pregnancy; Humans; Diabetes Mellitus, Type 2; alpha-Fetoproteins; Diabetes Mellitus, Type 1; Ammonia; Liver; Diabetes, Gestational; Inflammation; Albumins
PubMed: 37715985
DOI: 10.2478/enr-2023-0024 -
Pathology Oncology Research : POR Apr 2020Hepatocellular carcinoma (HCC) is one of the most malignant cancer with high morbidity and mortality which lead to a serious burden to society. AFP (alpha-fetoprotein)... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the most malignant cancer with high morbidity and mortality which lead to a serious burden to society. AFP (alpha-fetoprotein) is the most widely used serum biomarker to detect HCC worldwide. However, no AFP elevation have been found in many HCC and AFP analysis can't be used to screen HCC in these cases. Currently, many studies have been carried out to find reliable biomarker in diagnosing AFP-negative HCC. Such biomarker would help the diagnosis of AFP-negative HCC, ensuring the timely initiation of treatment. In this review, we highlight the important role of biomarkers that can differentiate AFP-negative HCCs, and discuss their potential clinical applications as biomarkers for the diagnosis of AFP-negative HCC.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Early Diagnosis; Humans; Liver Neoplasms; alpha-Fetoproteins
PubMed: 30661224
DOI: 10.1007/s12253-019-00585-5 -
The Journal of Clinical Investigation Jun 2023Many patients with hepatocellular carcinoma (HCC) do not respond to the first-line immune checkpoint inhibitor treatment. Immunization with effective cancer vaccines is...
Many patients with hepatocellular carcinoma (HCC) do not respond to the first-line immune checkpoint inhibitor treatment. Immunization with effective cancer vaccines is an attractive alternative approach to immunotherapy. However, its efficacy remains insufficiently evaluated in preclinical studies. Here, we investigated HCC-associated self/tumor antigen, α-fetoprotein-based (AFP-based) vaccine immunization for treating AFP (+) HCC mouse models. We found that AFP immunization effectively induced AFP-specific CD8+ T cells in vivo. However, these CD8+ T cells expressed exhaustion markers, including PD1, LAG3, and Tim3. Furthermore, the AFP vaccine effectively prevented c-MYC/Mcl1 HCC initiation when administered before tumor formation, while it was ineffective against full-blown c-MYC/Mcl1 tumors. Similarly, anti-PD1 and anti-PD-L1 monotherapy showed no efficacy in this murine HCC model. In striking contrast, AFP immunization combined with anti-PD-L1 treatment triggered significant inhibition of HCC progression in most liver tumor nodules, while in combination with anti-PD1, it induced slower tumor progression. Mechanistically, we demonstrated that HCC-intrinsic PD-L1 expression was the primary target of anti-PD-L1 in this combination therapy. Notably, the combination therapy had a similar therapeutic effect in the cMet/β-catenin mouse HCC model. These findings suggest that combining the AFP vaccine and immune checkpoint inhibitors may be effective for AFP (+) HCC treatment.
Topics: Mice; Animals; Carcinoma, Hepatocellular; Liver Neoplasms; Immune Checkpoint Inhibitors; alpha-Fetoproteins; Myeloid Cell Leukemia Sequence 1 Protein; CD8-Positive T-Lymphocytes; Cancer Vaccines
PubMed: 37040183
DOI: 10.1172/JCI163291 -
Trends in Immunology Jun 2022α-Fetoprotein (AFP) is a fetal glycoprotein produced by most human hepatocellular carcinoma tumors. Research has focused on its immunosuppressive properties in... (Review)
Review
α-Fetoprotein (AFP) is a fetal glycoprotein produced by most human hepatocellular carcinoma tumors. Research has focused on its immunosuppressive properties in pregnancy, autoimmunity, and cancer, and human AFP directly limits the viability and functionality of human natural killer (NK) cells, monocytes, and dendritic cells (DCs). AFP-altered DCs can promote the differentiation of naïve T cells into regulatory T cells. These properties may work to shield tumors from the immune system. Recent efforts to define the molecular characteristics of AFP identified key structural immunoregulatory domains and bioactive roles of AFP-bound ligands in immunomodulation. We propose that a key mechanism of AFP immunomodulation skews DC function through cellular metabolism. Delineating differences between fetal 'normal' AFP (nAFP) and tumor-derived AFP (tAFP) has uncovered a novel role for tAFP in altering metabolism via lipid-binding partners.
Topics: Carcinoma, Hepatocellular; Dendritic Cells; Female; Humans; Immunomodulation; Liver Neoplasms; Pregnancy; alpha-Fetoproteins
PubMed: 35550875
DOI: 10.1016/j.it.2022.04.001 -
Hepatology Communications May 2024Alpha-fetoprotein (AFP) is a glycoprotein that plays an important role in immune regulation with critical involvement in early human development and maintaining the... (Review)
Review
Alpha-fetoprotein (AFP) is a glycoprotein that plays an important role in immune regulation with critical involvement in early human development and maintaining the immune balance during pregnancy. Postfetal development, the regulatory mechanisms controlling AFP undergo a shift and AFP gene transcription is suppressed. Instead, these enhancers refocus their activity to maintain albumin gene transcription throughout adulthood. During the postnatal period, AFP expression can increase in the setting of hepatocyte injury, regeneration, and malignant transformation. It is the first oncoprotein discovered and is routinely used as part of a screening strategy for HCC. AFP has been shown to be a powerful prognostic biomarker, and multiple HCC prognosis models confirmed the independent prognostic utility of AFP. AFP is also a useful predictive biomarker for monitoring the treatment response of HCC. In addition to its role as a biomarker, AFP plays important roles in immune modulation to promote tumorigenesis and thus has been investigated as a therapeutic target in HCC. In this review article, we aim to provide an overview of AFP, encompassing the discovery, biological role, and utility as an HCC biomarker in combination with other biomarkers and how it impacts clinical practice and future direction.
Topics: Adult; Female; Humans; Pregnancy; alpha-Fetoproteins; Carcinogenesis; Carcinoma, Hepatocellular; Hepatocytes; Liver Neoplasms
PubMed: 38619448
DOI: 10.1097/HC9.0000000000000422 -
Clinical Gastroenterology and... Feb 2023α-fetoprotein (AFP), AFP Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP) in combination or in GALAD (Gender, Age,...
BACKGROUND & AIMS
α-fetoprotein (AFP), AFP Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP) in combination or in GALAD (Gender, Age, AFP-L3, AFP, and DCP) were tested for hepatocellular carcinoma (HCC) surveillance in retrospective cohort and case-control studies. However, there is a paucity of prospective data and no phase III biomarker studies from North American populations.
METHODS
We conducted a prospective specimen collection, retrospective blinded evaluation (PRoBE) cohort study in patients with cirrhosis enrolled in a 6-monthly surveillance with liver imaging and AFP. Blood samples were prospectively collected every 6 months and analyzed in a retrospective blinded fashion. True positive rate (TPR) and false positive rate (FPR) for any or early HCC were calculated within 6, 12, and 24 months of HCC diagnosis based on published thresholds for biomarkers individually, in combination and in GALAD and Hepatocellular Carcinoma Early Detection Screening (HES) scores. We calculated the area under the receiver operating curve and estimated TPR based on an optimal threshold at a fixed FPR of 10%.
RESULTS
The analysis was conducted in a cohort of 534 patients; 50 developed HCC (68% early) and 484 controls with negative imaging. GALAD had the highest TPR (63.6%, 73.8%, and 71.4% for all HCC, and 53.8%, 63.3%, and 61.8 % for early HCC within 6, 12, and 24 months, respectively) but an FPR of 21.5% to 22.9%. However, there were no differences in the area under the receiver operating curve among GALAD, HES, AFP-L3, or DCP. At a fixed 10% FPR, TPR for GALAD dropped (42.4%, 45.2%, and 46.9%) and was not different from HES (36.4%, 40.5%, and 40.8%) or AFP-L3 alone (39.4%, 45.2%, and 44.9%).
CONCLUSIONS
In a prospective cohort phase III biomarker study, GALAD was associated with a considerable improvement in sensitivity for HCC detection but an increase in false-positive results. GALAD performance was modest and not different from AFP-L3 alone or HES.
Topics: Humans; United States; Carcinoma, Hepatocellular; alpha-Fetoproteins; Liver Neoplasms; Retrospective Studies; Cohort Studies; Prospective Studies; Biomarkers; Prothrombin; Biomarkers, Tumor; Sensitivity and Specificity
PubMed: 35124267
DOI: 10.1016/j.cgh.2022.01.047 -
Canadian Journal of Gastroenterology &... 2018Hepatocarcinoma is one of the most prevalent gastroenterological cancers in the world with less effective therapy. As an oncofetal antigen and diagnostic marker for... (Review)
Review
Hepatocarcinoma is one of the most prevalent gastroenterological cancers in the world with less effective therapy. As an oncofetal antigen and diagnostic marker for liver cancer, alpha-fetoprotein (AFP) possesses a variety of biological functions. Except for its diagnosis in liver cancer, AFP has become a target for liver cancer immunotherapy. Although the immunogenicity of AFP is weak and it could induce the immune escapes through inhibiting the function of dendritic cells, natural killer cells, and T lymphocytes, AFP has attracted more attention in liver cancer immunotherapy. By in vitro modification, the immunogenicity and immune response of AFP could be enhanced. AFP-modified immune cell vaccine or peptide vaccine has displayed the specific antitumor immunity against AFP-positive tumor cells and laid a better foundation for the immunotherapy of liver cancer.
Topics: Animals; Cancer Vaccines; Carcinoma, Hepatocellular; Humans; Immunotherapy; Liver Neoplasms; Tumor Escape; alpha-Fetoproteins
PubMed: 29805966
DOI: 10.1155/2018/9049252