Tue Mar 16 2021

What is a Biomarker and How to Use Them?

A biomarker can be defined as “a biologic characteristic that can be measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or an intervention”1. In clinical practice, early diagnosis is the key for prompt management of a condition and a good prognosis. Biomarkers can be used in clinical practice for the screening and early diagnosis of various diseases and disorders. Moreover, as biomarker testing is non-invasive and cost-effective, testing for biomarkers is a convenient and reliable method of diagnosing a condition1. Besides diagnosis, biomarkers can also be used for monitoring treatment progression in a patient, determining recurrence risk of a disease, and assessing the prognosis of a condition1.

Clinical Biomarkers

Clinical biomarkers can be categorized into the following groups depending on their usage in clinical practice1:

  • Diagnostic biomarkers: This type of biomarker either detects or confirms the presence of a specific disease. These biomarkers could also be used to identify patients with the sub-type of a particular disease.
  • Monitoring biomarkers: This type of biomarker can be measured serially to assess the status of a disease for evidence of exposure to a medical treatment. These biomarkers can also be used to monitor the effect of a treatment on the health status of the patient.
  • Pharmacodynamic/Response biomarkers: When the level of a biomarker changes in response to exposure to a medical therapy or an environmental agent, it is known as a pharmacodynamic or response biomarker. This type of biomarker can help decide the best treatment options for a particular condition.
  • Predictive biomarkers: This type of biomarker can predict the degree of benefit a patient can have from a treatment plan, compared to their baseline condition. At the same time, a predictive biomarker can be used to predict the likelihood of a treatment plan working more favourably for a group of patients than other patients with the same disease.
  • Prognostic biomarker: This type of biomarker is used to predict the likelihood of disease recurrence, disease progression, or occurrence of a clinical event in patients with a specific disease.
  • Safety biomarker: This type of biomarker is measured before or after exposure to a medical intervention or environmental agent to determine the likelihood or presence or extent of toxicity, as an adverse reaction to the medical intervention or agent.
  • Susceptibility/Risk biomarker: This type of biomarker helps to assess the potential risk for developing a disease in an individual who does not currently have a clinically apparent disease.

Most Popular Unspecific Biomarkers: CRP and suPAR

C-reactive Protein (CRP): CRP is an acute-phase inflammatory protein. During inflammatory conditions such as rheumatoid arthritis, some cardiovascular diseases, and infection, the levels of CRP in the bloodstream elevate. The plasma concentration of CRP deviates by at least 25% during inflammatory disorders2. The highest concentrations of CRP are found in serum, with some bacterial infections causing CRP levels to go up to 1,000-fold. However, as the level of inflammation within the body decreases, CRP values decrease exponentially over 18–20 h. CRP plasma levels can increase from around 1 µg/mL to over 500 µg/mL within 24–72 h in case of severe tissue damage such as trauma and progressive cancer2.

Soluble urokinase plasminogen activator receptor (suPAR): suPAR is the soluble, circulatory form of the membrane-bound protein- urokinase plasminogen activator receptor (uPAR). In normal conditions, uPAR is found in several immunologically active cells of the body. During inflammation, the concentration of suPAR increases in the bloodstream. Research shows that the concentration of suPAR in blood correlates to the severity of a disease. Hence, suPAR can be used for monitoring disease progression and effect of treatment3.
In healthy individuals, suPAR level is usually in the range of 1-3 ng/ml. In presence of inflammation, suPAR levels are elevated, but in most cases remain under 3 ng/ml. In critically ill patients, suPAR levels can rise above 10 ng/ml4.

Biomarkers to Detect Different Diseases

The important biomarkers currently used in clinical practice for screening and diagnosis of different diseases are listed as follows5,6,7,8,9,10,11,12 :

Biomarkers for Alzheimer’s

  • Amyloid beta
  • Tau protein
  • Phosphorylated tau

Biomarkers for Cancer (LINK)

  • Prostate-specific antigen (PSA)
  • Carcinoembryonic antigen (CEA)
  • HER2
  • Alfa-fetoprotein

Biomarkers for Cardiac Disease (LINK)

  • B-type natriuretic peptide (BNP)
  • Troponin
  • C-reactive Protein
  • Myeloperoxidase (MPO)
  • Fibrinogen

Biomarkers in neurodegenerative diseases

  • Tau
  • Phosphorylated tau
  • Amyloid beta

Biomarkers of liver function (LINK)

  • Alanine amino transferase (ALT)
  • Aspartate amino transferase (AST)
  • Alkaline Phosphatase (ALP)
  • Serum Bilirubin

Biomarkers for acute kidney injury (LINK)

  • Neutrophil gelatinase-associated lipocalin (NGAL)
  • Kidney injury molecule-1 (KIM 1)
  • Cystatin C
  • IL-18

Biomarkers for brain injury

  • Glial fibrillary acidic protein
  • S100B
  • UCHL-1

Biomarkers for heart failure

  • B-type natriuretic peptide (BNP)
  • Galectin-3
  • Neutrophil gelatinase-associated lipocalin (NGAL)
  • Mid-regional pro-adrenomedullin (MR-ProADM)

Biomarkers for stress

  • Cortisol
  • Adrenaline
  • Noradrenaline
  • DHEA

Biomarkers for sepsis (LINK)

  • C-reactive Protein
  • Procalcitonin

Inflammatory biomarkers (LINK)

  • Cytokines
  • C-reactive Protein
  • Serum Amyloid A
  • COX-2 Expression

Biomarkers in Other Areas

Biomarkers measured for other health issues are as follows13,14,15 :

Biomarkers for ageing (LINK)

  • DNA repair
  • Telomeres
  • Epigenetic modifications
  • Cell senescence

Biomarkers for wound healing (LINK)

  • Tissue biomarkers- c-myc and B-catenin
  • Metalloproteinase enzymes (wound fluid biomarkers)
  • CD 34+/CD45-

Biomarkers in medicine (LINK)

  • Cholesterol
  • Triglycerides
  • HDL-cholesterol
  • LDL-cholesterol
  • C-Peptide

suPAR as a Biomarker: How to use it across diseases

The biomarker suPAR is the soluble form of the cell membrane-bound protein uPAR, which is expressed mainly on leucocytes (white blood cells) including neutrophils, lymphocytes, monocytes, and macrophages. Leucocytes form an integral part of the body’s immune system and are involved in the body’s inflammatory response to diseases and injuries. All human beings have a baseline level of suPAR, which is low but increases with age. suPAR levels in the body are elevated in the presence of diseases16,17.

Scientific studies have shown that suPAR is associated with a number of chronic diseases (including cardiovascular, hepatic, renal, and pulmonary diseases). Moreover, suPAR level is a predictor of a negative outcome (NPV) of various infectious diseases (tuberculosis, HIV, malaria, sepsis, meningitis, pneumonia). suPAR can be used as a prognostic as well as a predictive biomarker of various conditions. The concentration of suPAR in the bloodstream can also be monitored to assess the progression of a disease and evaluate efficacy of a treatment plan18,19,20,21.

Kinetics of suPAR

In normal conditions, the suPAR blood level is stable with no diurnal variation or changes following fasting. suPAR can be measured in blood, plasma, urine, cerebrospinal fluid, ascites fluid and pleural fluid22. The level of suPAR increases and decreases with progression and improvement of a disease, respectively, but more slowly compared to e.g. C-reactive protein (CRP).

Plasma suPAR is a robust biomarker which undergoes minimal changes during laboratory handling and storage. Plasma suPAR level remains stable for at least 24 hours at room temperature and for at least five repeated freeze/thaw cycles23.

suPAR in Clinical Practice

In the first week of febrile neutropenia, serum suPAR levels have been found to have a sensitivity of 100%, a specificity of 69%, a negative predictive value (NPV) of 100%, and a positive predictive value (PPV) of 70%.Currently, no alternative to suPAR with the same strong NPV have been found. High NPV and PPV (87% and 91%, respectively with a cut of value of 2.8ng/mL) have also been found when testing the prognosis of patients with systemic inflammatory response syndrome (SIRS) patients.34 In children with SIRS, a NPV and PPV, both of 96% for suPAR have been reported24,25.

Studies have shown that increased levels of suPAR can predict disease outcome in various forms of cancer and infectious diseases. In chronic liver disease, with progressive liver fibrosis, the suPAR level is increased and correlates with poor prognosis. Also, cirrhotic patients have higher suPAR levels than non-cirrhotic patients. Circulating suPAR levels closely correlate with liver function, fibrosis markers, systemic inflammation and renal function26,27.

1. Califf RM. Biomarker definitions and their applications. Exp Biol Med (Maywood). 2018;243(3):213–221. doi:10.1177/1535370217750088.
2. Sproston NR, Ashworth JJ. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front Immunol. 2018;9: 754. Published 2018 Apr 13. doi:10.3389/fimmu.2018.00754.
3. da Silva et.al. Evaluation of the diagnostic potential of uPAR as a biomarker in renal biopsies of patients with FSGS. Disease Markers. 2019.
4. The diagnostic value of soluble urokinase plasminogen activator receptor (suPAR) compared to C-reactive protein (CRP) and procalcitonin (PCT) in children with systemic inflammatory response syndrome (SIRS), Melis Şirinoğlu et al, 2016, Journal of Infection and Chemotherapy 23
5. Sharma N, Singh AN. Exploring Biomarkers for Alzheimer’s Disease. J Clin Diagn Res. 2016;10(7):KE01–KE6. doi:10.7860/JCDR/2016/18828.8166
6. Hala et.al. Cancer Biomarkers: Role of Biomarkers in Medicine, Mu Wang and Frank A. Witzmann. IntechOpen Books. 2016. https://www.intechopen.com/books/role-of-biomarkers-in-medicine/cancer-biomarkers
7. Huang et.al. Biomarkers of cardiovascular disease. Disease Markers. 2017.
8. Gowda S, Desai PB, Kulkarni S. A review on laboratory liver function tests. The Pan African Medical Journal. 2009; 3: 17.
9. Alge JL, Arthur JM. Biomarkers of AKI: A review of mechanistic relevance and potential therapeutic implications. Clinical Journal of American Society of Nephrology. 2015. 10(1).
10. Dadas A, Washington J, Diaz-Arrastia R, Janigro D. Biomarkers in traumatic brain injury (TBI): a review. Neuropsychiatr Dis Treat. 2018;14: 2989–3000. Published 2018 Nov 8. doi:10.2147/NDT.S125620
11. Nelson GE, Mave V, Gupta A. Biomarkers for sepsis: A review with special attention to India. Blood Stream Infections. 2014.
12. Brenner et.al. A review of the application of inflammatory biomarkers in epidemiologic cancer research. Cancer Epidemiology, Biomarkers & Prevention. 2014. 23(9).
13. Xia X, Chen W, McDermott J, Han JJ. Molecular and phenotypic biomarkers of aging. F1000Res. 2017;6: 860. Published 2017 Jun 9. doi:10.12688/f1000research.10692.1
14. Lindley et.al. Biology and biomarkers for wound healing. Plastic and Reconstructive Surgery. 2017. 138(3).
15. Mayeux R. Biomarkers: Potential Uses and Limitations. NeuroRx. 2004 Apr; 1(2): 182–188.
16. Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3: 932–43.
17. Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 2010; 11: 23–36.
18. Eugen-Olsen, J. et al. Circulating soluble urokinase plasminogen activator receptorpredicts cancer, cardiovascular disease, diabetes and mortality in the generalpopulation. J. Intern. Med. 2010;268, 296–308.
19. Reichsoellner M, Raggam RB, Wagner J, Krause R, Hoenigl M. Clinical evaluation of multiple inflammation biomarkers for diagnosis and prognosis for patients with systemic inflammatory response syndrome. Journal of clinical microbiology 2014;52:4063-6.
20. Gumus A, Altintas N, Cinarka H, et al. Soluble urokinase-type plasminogen activator receptor is a novel biomarker predicting acute exacerbation in COPD. International journal of chronic obstructive pulmonary disease 2015;10:357-65.
21. Persson M, Ostling G, Smith G, et al. Soluble urokinase plasminogen activator receptor: a risk factor for carotid plaque, stroke, and coronary artery disease. Stroke; a journal of cerebral circulation 2014;45: 18-23.
22. Thunø M, Macho B, Eugen-Olsen J. suPAR: The molecular crystal ball. Dis Markers. 2009;27(3):157-72. 2. Eugen-Olsen, J. et al. Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J. Intern. Med. 2010;268, 296–308.
23. Development and Validation of a Multiplex Add-On Assay for Sepsis Biomarkers Using xMAP Technology Kristian Kofoed,1,2* Uffe Vest Schneider,1 Troels Scheel,1 Ove Andersen,1,2 and Jesper Eugen-Olsen1, Clinical Chemistry 52:7 1284–1293 (2006)
24. Rasmussen LJ, et al. Soluble urokinase plasminogen activator receptor (suPAR) in acute care: a strong marker of disease presence and severity, readmission and mortality. A retrospective cohort study. Emerg Med J.2016 33(11):769-775.
25. The diagnostic and prognostic significance of soluble urokinase plasminogen activator receptor in systemic inflammatory response syndrome, Yilmaz et al, clinical Biochemistry, 2011;44(14-15):1227-1230
26. Feldman. Sleisenger and Fordtran’s gastrointestinal and liver disease. 9th ed. Philadelphia, PA, United States: Saunders: an imprint of Elsevier, 2010.
27. Circulating soluble urokinase plasminogen activator is elevated in patients with chronic liver disease, discriminates stage and aetiology of cirrhosis and predicts prognosis, Henning W. Zimmermann, Alexander Koch, Sebastian Seidler, Christian Trautwein and Frank Tacke, Liver International ISSN 1478-3223

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