Liver cancer ranks 5th among the cancers that occur commonly and ranks third among the causes of cancer-related deaths globally. Liver cancer that arises from hepatocytes is primary liver cancer whereas, that metastasizes from other organs is known as secondary liver cancer. Of all the primary liver malignancies, hepatocellular carcinoma (HCC) accounts for 75–85 %. In the past 30 years, there has been more than 75% increase in the incidence of HCC worldwide, and this growth is anticipated to continue in the near future. Unfortunately, during this period, the survival rates for people with HCC have remained alarmingly low. There are several causes for the high mortality rates of HCC, but one of the main reasons is the delayed detection of cancer at the early stages of the disease [1].
In this blog, we will delve into the application of biomarkers in the early detection of HCC patients.
What are the possible diagnostic methods for HCC?
Patients who are at a high risk of developing HCC should be monitored continuously for the early detection of HCC. They include all patients with cirrhosis attributable to non-viral causes (alcoholic liver disease [ALD], and non-alcoholic fatty liver disease [NAFLD] or viral hepatitis - hepatitis B or hepatitis C). Additionally, specific population of individuals with non-cirrhotic hepatitis B and those with a family history of HCC may also be monitored. Ideally, this HCC surveillance program should be offered to patients in whom the early discovery of the disease can help the reception of curative therapy. The emerging diagnostic tools that help in HCC surveillance are:
Recording a detailed personal and familial history
Routine blood investigations
Liver function tests
Histopathological analysis of the biopsy sample of the liver tissue
Magnetic resonance imaging (MRI)
Computed tomography
Positron emission tomography (PET)
Ultrasonography
However, all these tests have their limitations. Blood investigations and liver function tests may provide only tentative diagnosis as they get affected in other conditions like cirrhosis and hepatitis. Imaging modalities can result in radiation damage to the patient. So the recent advances in the diagnostic field have focused on the application of biomarkers in the early detection of liver cancer [2].
What are biomarkers?
A biomarker is a molecular, cellular, or metabolic alteration that can be precisely and frequently evaluated. They are used to identify and monitor pathological, physiological, and pharmacological response processes. Biomarkers include genes, DNA, RNA, platelets, enzymes, hormones, and other biomolecules like proteins, carbohydrates and lipids. It can be of any substance that helps in the diagnosis of a condition, modifications of biological processes or structures, or distinguishing characteristics. There are different types of biomarkers and they can be further classified. [3].
How do these biomarkers help in the early detection of hcc?
For the diagnosis of liver cancer, biomarkers can be extracted from blood, saliva, pus, and cerebrospinal fluid (CSF). The ideal method is the collection of samples from blood because it is a less invasive procedure and does not require lumbar puncture (a procedure used to collect CSF).
This method also has other benefits as it is relatively inexpensive and if required can be repeated to assess the course of the disease. Additionally, it can be also used for screening families or relatives of patients who have a familial history of HCC.
Alpha‐Fetoprotein: The primary serological diagnostic marker for detecting HCC is AFP, a protein belonging to the albumin family. According to the literature it is elevated in almost 60% to 80% of HCCs. Advantages include low cost, wide availability, ease of measuring the levels and its strong association with HCC. Limitations include its low specificity as it is also elevated in other conditions such as liver cirrhosis, chronic hepatitis, and several neurodegenerative disorders. So, American Association for the Study of Liver Diseases (AASLD) has recommended its use as an accessory diagnostic tool in liver cancer detection combined with imaging techniques.
AFP ‐ L3: The limitations associated with alpha fetoprotein are overcome by AFP-L3, an isotope of AFP. According to the literature, it was shown to be more specifically associated with HCC compared to AFP. The food and drug administration (FDA) approved this biomarker for the assessment of liver cancer as a part of the GALAD score (a scale that helps to detect HCC based on Gender, age, AFP L3, and Des‐Gamma‐Carboxy Prothrombin). The limitation of this biomarker is that, it has limited sensitivity even though its specificity is more compared to AFP.
Des-Gamma‐Carboxy Prothrombin: Another serum biomarker for HCC is des-gamma-carboxy prothrombin (DCP). It is a prothrombin precursor and, in HCC, this will undergo metabolism in an abnormal way. Patients with HCC have been reported to have increased levels of DCP. DCP is gaining more importance as a possible biomarker for HCC, according to the available data. Levels of DCP are correlated with the HCC stage and survival and it is more sensitive than AFP for this disease detection.
Heparin sulphate proteoglycan glipican-3 (GPC3) is another biomarker that is increased in HCC. Other biomarkers like osteopontin, midkine, dickkopf-1, squamous cell carcinoma antigen, and fibronectin are also promising for the early detection of HCC [4].
Take home message!
As HCC is difficult to identify in its early stages, we need screening methods that are highly sensitive. Biomarkers are definitely a useful tool in differentiating HCC from other liver diseases which have the same clinical features. The efficacy of these potential indicators as diagnostic tools will be further defined by prospective studies in the future. A new era of early tumor discovery, higher rates of curative therapy, and ultimately improved survival rates for patients with HCC are anticipated as a result of advancements in screening and surveillance.
References
1. N. Adeniji and R. Dhanasekaran, “Current and Emerging Tools for Hepatocellular Carcinoma Surveillance,” Hepatol Commun, vol. 5, no. 12, pp. 1972–1986, Sep. 2021, doi: 10.1002/hep4.1823.
2. Y.-S. Lim, “Role of Tumor Biomarkers in the Surveillance of Hepatocellular Carcinoma,” Korean J Gastroenterol, vol. 78, no. 5, pp. 284–288, Nov. 2021, doi: 10.4166/kjg.2021.137.
3. V. L. Chen and P. Sharma, “Role of Biomarkers and Biopsy in Hepatocellular Carcinoma,” Clin Liver Dis, vol. 24, no. 4, pp. 577–590, Nov. 2020, doi: 10.1016/j.cld.2020.07.001.
4. P. Johnson, Q. Zhou, D. Y. Dao, and Y. M. D. Lo, “Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma,” Nat Rev Gastroenterol Hepatol, vol. 19, no. 10, pp. 670–681, Oct. 2022, doi: 10.1038/s41575-022-00620-y.
