Inflammatory Biomarker Series: Antioxidants
So far in our inflammatory biomarker series, we have considered the clinical significance of measuring rheumatoid factor (RF) and C-reactive protein (CRP) to detect inflammation. Inflammation, either chronic or acute, is the body’s immune response to protect against harmful stimuli such as damaged cells, irritants or pathogens and can be present in a range of diseases and conditions.1 Measuring inflammatory biomarkers can assist clinicians in the identification of a particular disease or can provide a marker of treatment response. In this blog, we consider the role of antioxidants and identify relevant biomarkers which may be linked to inflammatory states.
What is an antioxidant?
An antioxidant is a molecule that inhibits the oxidation of other molecules. Oxidation is a chemical reaction that produces free radicals, which are groups of very reactive molecules that can interrupt important cellular processes. Antioxidants are commonly referenced with regards to food, however antioxidants are also found in the body in the form of enzymes. Their purpose is to protect against the effects of oxidative stress to reduce damage from free radicals.
What is the link between antioxidants and inflammation?
Oxidative stress and the inflammation associated with it are the cause of most human disease. This would suggest that free radicals are implicated in many disease states for example rheumatoid arthritis, asthma, stroke, or cancer. Therefore antioxidants are important to protect against oxidative damage, thus reducing the risk of inflammation. There are a number of antioxidants which play a protective role the body, such as ferritin, superoxide dismutase, transferrin, uric acid and glutathione reductase.
Ferritin is responsible for storing iron and releasing it when required. Ordinarily, ferritin is found inside blood cells with only a small amount circulating in the blood. Ferritin is clinically significant at both high and low levels. Low levels of ferritin can highlight an iron deficiency which causes anaemia. Whereas elevated levels of ferritin can be a result of conditions such as rheumatoid arthritis, haemochromatosis, liver disease, metabolic syndrome, type 2 diabetes and renal failure.2 As ferritin is an acute phase reactant, levels will be elevated in any inflammatory state within the body.3
Transferrin is a protein that is responsible for binding and transporting iron in the blood. Transferrin acts as a preventative antioxidant as it binds with free iron, removing it from the bloodstream. This is a critical function, as free iron can stimulate the production of harmful free radicals. As transferrin is a negative acute phase protein, lower levels are associated with inflammatory conditions.7
Superoxide is a by-product of oxygen metabolism and is one of the most damaging free radicals in the body as it can cause cell damage. Superoxide Dismutase (SOD) is an enzyme which catalyses the breakdown of superoxide into a less damaging oxygen or hydrogen peroxide. Therefore SOD preforms a vital defensive function to reduce oxidative stress.4 Extensive research exists which links oxidative stress to chronic inflammation, which can be a contributing factor to diabetes, arthritis, cardiovascular disease and cancer.5 Therefore if levels of superoxide dismutase are low, patients are at risk inflammation, for example, SOD levels are significantly less in rheumatoid arthritis patients.6
Glutathione reductase is found in red blood cells and plays a key role in maintaining cell function and preventing oxidative stress in human cells. Reduced levels of glutathione reductase can contribute to the prevalence of inflammatory states, suggesting that adequate levels of glutathione reductase are essential for optimal function of the immune system. 7, 8
Uric acid is a waste product produced when the body breaks down chemical compounds called purines. It is a scavenging antioxidant that acts by inactivating free radicals. Elevated levels of uric acid is commonly associated with gout, a type of arthritis which is caused when crystals of sodium urate form inside joints causing rapid and painful inflammation.9 Other research has indicated that elevated levels of uric acid is associated with increased risk of cardiovascular disease.
Total Antioxidant Status (TAS)
TAS is a measurement of antioxidant function rather than quantity and considers the cumulative effect of all antioxidants present. The antioxidant defence system has many components, and a deficiency in any of these components can cause a reduction in the overall antioxidant status of an individual.10 Reduction in total antioxidant status has been implicated in several disease states including cancer, CVD, Arthritis and Alzheimer’s disease.
As demonstrated above, different types of antioxidants can help reduce different types of inflammation. Antioxidant tests can be requested from any doctor, who may also review dietary intake, investigate any symptoms and advise if testing is required. If antioxidant levels are found to be inadequate, improving them can be easily done through dietary changes, and can help reduce a body’s overall inflammation.
For health professionals
Randox Laboratories offer a range of diagnostic reagents for antioxidant testing to assist in the diagnosis of inflammatory diseases. Randox offer a complete diagnostic package with applications for a range of biochemistry analysers and a selection of kit sizes, controls and calibrators available. Available tests include: Ferritin, Transferrin, Superoxide Dismutase (Ransod), Glutathione Reductase, Uric Acid, and Total Antioxidant Status (TAS).
- Nordqvist, C., Inflammation: Causes, Symptoms and Treatment. Medical News Today, 2015, https://goo.gl/rT4WS9 (accessed 16 January 2017)
- Koperdanova, M., Interpreting raised serum ferritin levels, British Medical Journal, 2015, https://doi.org/10.1136/bmj.h3692 (accessed 2 February 2017)
- Nall, R. Ferritin Level Blood Test, Health Line, 2015, https://goo.gl/XGcW9P (accessed 2 February 2017)
- Yasui, K. and Baba, A., Therapeutic potential of superoxide dismutase (SOD) for resolution of inflammation. Inflammation Research. Vol.55, No.9, pp.359-363, 2006, 1007/s00011-006-5195-y (accessed 2 February 2017)
- Reuter, S., Gupta, S.C., Chaturvedi, M.M., Aggarwal, B.B., Oxidative stress, inflammation and cancer: How are they linked? Free Radic Biol Med. 2010, 1; 49(11):1603-1616 https://goo.gl/Uez3JZ (accessed 2 February 2017)
- Bae SC, Kim SJ, Sung MK., Inadequate antioxidant nutrient intake and altered plasma antioxidant status of rheumatoid arthritis patients. J Am Coll Nutr. 2003 Aug;22(4):311-5
- Reynolds, B., Glutathione for inflammatory respsonse, FX Medicine, 2015, Available from: https://goo.gl/2YAv5l (accessed 3 February 2017)
- Morris, G., Anderson, G., Dean, O. et al., The glutathione system: a new drug target in neuroimmune disorders. Mol Neurobiol 2014;50(3):1059-1084, Available from: https://goo.gl/PDSgwv (accessed 3 February 2017)
- Malaghan Institute, Uric acid – a new look at an old marker of inflammation, Malaghan Institute of Medical Research, 2013, Available from: https://goo.gl/P6NfXP
- Li, Y., Browne, R.W., Bonner, M.R., Deng, F., Tian, L., Mu, L., Positive Relationship between Total Antioxidant Status and Chemokines Observed in Adults. Oxid Med Cell Longev. 2014, Available from: https://goo.gl/rmj5MB (accessed 9 February 2017)
What are inflammatory biomarkers?
The purpose of measuring an inflammatory biomarker is to detect inflammation, which can assist clinicians in the identification of a particular disease or provide a marker of treatment response. Inflammation, either chronic or acute, is the body’s immune response to protect against harmful stimuli such as damaged cells, irritants or pathogens.1 When inflammation occurs in the body, extra protein is released from the site of inflammation and circulates in the bloodstream.2 It is these proteins, or antibodies, which clinicians are testing for in the blood as they can indicate if inflammation is present.
Like many inflammatory biomarkers, such as rheumatoid factor (RF), C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), further tests will be required as testing for these tests alone does not provide a clearly defined diagnosis. However inflammatory biomarker tests can provide clinicians with a good indication of what may be wrong with a patient, which is why they are commonly tested for in a clinical setting.
What is Rheumatoid Factor?
Rheumatoid factor (RF) is an autoantibody which can target and damage healthy body tissue and in turn cause inflammatory symptoms.3 It is uncommon for this antibody to be present in healthy individuals, which is why it is a beneficial test to aid the diagnostic process. In particular, rheumatoid factor can be used as an inflammatory biomarker to assist in the diagnosis of rheumatoid arthritis (RA). However the rheumatoid factor antibody can also be present in healthy individuals or patients with systemic lupus erythematosus, liver cirrhosis, Sjögren’s Syndrome, Hepatitis and other conditions.4 If a test detects rheumatoid factor levels above 14 IU/ml, this is considered abnormally high.3
What is Rheumatoid Arthritis?
Rheumatoid arthritis is an autoimmune disease which attacks the lining tissue of joints, resulting in chronic inflammation. This disease commonly affects the hands, feet and wrists, with symptoms causing pain, fatigue and loss of bodily function and over time may even lead to multiple organ damage.5 Although diagnosis of rheumatoid arthritis requires a physical examination, testing for rheumatoid factor can be beneficial to assist in the diagnosis of this disease. Other blood tests that can be used to detect biomarkers associated with rheumatoid arthritis include C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IgA, IgG, IgM and anti-cyclic citrullinated peptide (anti-CCP).
For health professionals
Randox Laboratories offer a leading portfolio of diagnostic reagents which includes a test for rheumatoid factor, with applications available for a range of biochemistry analysers. With a measuring range of 6.72 – 104 lU/ml, this assay can comfortably detect levels outside the normal range. Randox offer a complete diagnostic package for the screening of rheumatoid factor with a range of kit sizes, controls and calibrators available. Other inflammatory biomarker tests available from Randox include CRP, High Sensitivity CRP, Full Range CRP, IgA, IgG and IgM.
1. Nordqvist, C. Inflammation: Causes, Symptoms and Treatment. Medical News Today, https://goo.gl/rT4WS9 (accessed 16 January 2017)
2. Harding, M., Blood Tests to Detect Inflammation, Patient, 2015, https://goo.gl/F4OGrz, (accessed 16 January 2017)
3. Shiel, W. C., Rheumatoid Factor (RF), MedicineNet, 2016, https://goo.gl/XPA69u 2016 (accessed 16 January 2017)
4. Rheumatoid Arthritis Organisation, Rheumatoid Factor Test, Rheumatoid Arthritis Organisation, 2016, https://goo.gl/JujE5a
5. Gibofsky, A. Overview of Epidemiology, Pathophysiology and Diagnosis of Rheumatoid Arthritis. The American Journal of Managed Care. Vol.18, No.13. p.295-302, 2012
The answer to this common myth is no. Let us tell you why…
As a condition that usually manifests later in life, type 2 diabetes is viewed by many as a self-inflicted disease caused by eating too much sugar and being overweight. Although obesity is strongly associated with type 2 diabetes it isn’t the only cause. In fact, many people of a healthy weight have type 2 diabetes, and similarly many overweight people do not. This is because an individual’s metabolic health can be affected by factors other than their weight.
Firstly, let’s define metabolic health; metabolic health refers to the body’s health at a cellular function, and one aspect of this is the body’s ability to utilise nutrients for energy. Within this insulin has an important function; insulin is a hormone produced by the pancreas and used by the body to regulate how glucose is used and stored. In some individuals, however, this is not the case; their pancreas may either not produce enough insulin, or may not be able to effectively use the insulin it produces, known as insulin sensitivity. High blood sugar level and type 2 diabetes is the effect of this.
Whilst obesity and lack of exercise are 2 of the most common reasons affecting metabolic state and causing type 2 diabetes, it is important to note that approximately 1 in 3 type 2 diabetics are undiagnosed. Therefore the causal factors of these individuals are not included in the statistics and therefore not accounted for in this statement. Other causal factors include family history, ethnicity, age, stress, inflammation, poor diet and visceral fat.
Let’s talk about a few of these factors…
Family history & ethnicity – Do genetics play a role?
Risk factors of type 2 diabetes includes family history and ethnicity; research(1) has found that there is a 1 in 7 risk of type 2 diabetes for children whose parents were diagnosed before the age of 50, and 1 in 2 risk for children if both parents have type 2 diabetes. Furthermore, research(2) has linked genetic mutation of the HMGA1 gene to an increased risk of type 2 diabetes in white Europeans; the study found that defects in the HMGA1 gene led to a drop in the body’s ability to make insulin receptors, thus leading to insulin resistance. In fact, 1 in 10 study participants with type 2 diabetes had a genetic mutation of the gene. Furthermore certain ethnic groups have been linked to increased risk of type 2 diabetes i.e. African Americans, Native Americans, Hispanic Americans and Asian Americans; some believe this may be due to genetics.
When the body is under stress, stress hormones such as cortisol are released. These hormones can affect the body’s blood glucose levels; for example, one of the primary functions of cortisol is to provide an immediate source of energy for the body, resulting in an increase of glucose supply to the blood. Individuals suffering chronic stress therefore have a constant production of cortisol, and chronically increased blood glucose levels as a result. This increases the risk of type 2 diabetes.
Chronic stress can lead to inflammation, which is another risk factor in the development of type 2 diabetes.
As the body’s natural response to injury, inflammation is the initial step in the healing process. Opening the blood vessels to allow free movement of the body’s natural healing substances to the affected site, it offers the body protection and fights off foreign substances such as germs and toxins. Inflammation is necessary to rid infections and heal wounds, however if the body suffers a chronic state of inflammation it can have damaging effects; chronic inflammation is caused by autoimmune conditions, allergies, chronic stress and conditions such as Crohn’s disease, and is linked to major diseases such as heart disease, arthritis and certain cancers. The link with type 2 diabetes is a result of inflammation causing insulin resistance, increasing the risk of type 2 diabetes.
Abdominal visceral fat
Abdominal visceral fat is the fat which surrounds the internal organs in the abdominal cavity. High levels of abdominal visceral fat are associated with insulin resistance and therefore, high risk of diabetes. Abdominal visceral fat can be found in individuals of all shapes and sizes, and regardless of ‘healthy’ BMI high visceral fat levels can still occur. This is because BMI doesn’t take into account muscle mass or other factors including gender and ethnicity. This presents an issue as those with a ‘healthy’ BMI may unknowingly still be at risk of diabetes. Similarly those with high muscle mass, who are determined ‘overweight’ based on BMI, may worry that they are at risk of diabetes, when in fact their weight isn’t putting them at risk. Determining levels of abdominal visceral fat is a much better indication of health than BMI.
Overall risk of type 2 diabetes is correlated with genetic, environmental and lifestyle factors. Whilst some impact more than others, it is important to recognise that there are numerous factors related to type 2 diabetes, and rid the myth that obesity and a high sugar diet high are the only causal factors.
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(1) American Diabetes Association (2014) Genetics of Diabetes. Found online at diabetes.org/diabetes-basics/genetics-of-diabetes.html
(2) Brunetti et al (2011) Functional Variants of the HMGA1 Gene and Type 2 Diabetes Mellitus. Journal of the American Medical Association (JAMA); 305 (9):903-912.