Breaking Down The Different Markers Of Inflammation

Just about everyone with thyroid and autoimmune thyroid conditions have some type of inflammatory process.  This is especially true with those patients with Graves’ Disease and Hashimoto’s Thyroiditis.  And while the inflammatory markers on a blood test or stool panel won’t always be positive in the presence of inflammation, I still thought it would be beneficial to discuss some of the more important markers which relate to inflammation.

Before talking about the different inflammatory markers, I’d like to briefly discuss the inflammatory process, as this will help you to better understand the purpose behind testing for these markers.  First of all, why does someone experience inflammation?  The inflammatory process occurs when someone is exposed to a trauma, infection, food allergen, toxin, or something else that puts stress on the body.  Without going into too much detail, let’s look at an example of what happens when someone is exposed to a bacterial infection. In this situation there will be an activation of white blood cells, along with the release of something called arachidonic acid.  The arachidonic acid will lead to inflammatory substances known as leukotrienes and prostaglandins, and this in turn will stimulate neutrophils, which are a type of white blood cell in your body.  In fact, when you get a complete blood count with differential one of the things it will test for is neutrophils, and if the neutrophils are elevated, then this usually indicates an acute inflammatory process.

In any case, inflammation not only results in an increase in neutrophils, but it can also cause an increase in free radicals, which causes oxidative stress and tissue damage.  And your body will also release proinflammatory cytokines, which I’ve discussed in other articles as being a factor in autoimmunity.  This process also involves something called nuclear factor kappa B (NFkB), which results in more inflammation, and one of the problems with autoimmune conditions is that NFkB gets chronically upregulated.  I spoke about NFkB in greater detail in a past blog post entitled “The Role of Cytokines In Autoimmune Thyroid Conditions”.

Hopefully you have a better understanding of the inflammatory process.  Now I’d like to go ahead and talk about the different inflammatory markers:

C-reactive protein.  C-reactive protein (CRP) is one of the main inflammatory markers commonly tested for by healthcare professionals.  It increases as interleukin 6 (IL6) is secreted by immune system cells, with an example being macrophages.  IL6 is a proinflammatory cytokine, which I’ll discuss a little later.  CRP is not a specific test.  In other words, if it is positive it means you have inflammation, but it won’t tell you where the inflammation is located.  Ideally you want the levels to be less than 1.0 mg/L, but any value greater than 3.0 mg/L doesn’t only mean that the person has a good amount of inflammation, but it also might mean that you have an increased risk of developing cardiovascular disease (1).  When getting this test it’s best to order “high sensitivity” C-Reactive protein, also known as hs-CRP.

Reference range: Most labs use a reference range of 1.0 to 3.0 mg/L, and while greater than 3.0 mg/L seems to be a cardiovascular risk, ideally you want to see this less than 1.0 mg/L.

Erythrocyte sedimentation rate (ESR).  This is another inflammatory marker commonly recommended by healthcare professionals, and this marker represents the rate at which red blood cells sediment in a one hour period.  Like CRP, an elevated ESR confirms the presence of inflammation, but it doesn’t pinpoint specifically where the inflammation is in the body.  CRP is usually preferred because these levels increase in the blood quicker after the inflammatory process begins.

Reference range: The range will vary depending on the age and gender, as most labs use a reference range less than 15 mm/hr for men under 50 years old, less than 20 mm/hr for women under 50 years old, less than 20 mm/hr for men over 50 years old, and less than 30 mm/hr for women over 50 years old (2).

Fibrinogen.  This is a protein produced by the liver, and it helps to stop bleeding through the formation of blood clots.  This marker isn’t commonly used to measure inflammation, although it frequently elevates in the presence of inflammation.

Reference range: Most labs use a reference range of 200 to 400 mg/dL

Calprotectin.  Calprotectin is a marker tested in the stool that is used to detect intestinal inflammation.  It is a calcium-binding protein that is found in large amounts in neutrophils, and during inflammation, calprotectin is released from the activated neutrophils (3).  Although you can’t use calprotectin by itself to diagnose a certain condition, it can help to differentiate between inflammatory bowel disease (i.e. Crohn’s disease and ulcerative colitis) and non-inflammatory conditions (4) (5).  It can also be used to monitor the progress of someone with inflammatory bowel disease (IBD).  Just keep in mind that calprotectin can increase with certain gut infections (which can of course cause intestinal inflammation but doesn’t necessarily mean that someone has IBD), as well as with colorectal cancer (6).  However, calprotectin is usually normal or very low in those with irritable bowel syndrome (7).  So if someone has high calprotectin then they have some type of intestinal inflammation, perhaps IBD, and most likely not IBS.  On the other hand, if someone has normal calprotectin then they probably don’t have intestinal inflammation.

It’s important to know that the intake of non-steroidal anti-inflammatory drugs (NSAIDS) increases calprotectin levels (8) (9).  Also, since intestinal inflammation is more common in those with an increased body mass index (BMI), it shouldn’t be surprising that elevated calprotectin is associated with obesity (10) (11) (12).  Although the focus here is on fecal calprotectin levels, there is evidence that serum calprotectin is increased in those with papillary thyroid carcinoma, and significantly decreases after total thyroidectomy (13).

Reference Range: The labs I’m familiar with use a reference range of less than 50 mcg/g

Lactoferrin.  Fecal lactoferrin can also be a useful marker for determining if someone has intestinal inflammation.  It is an iron-binding protein, which comes mainly from neutrophils (14).  Lactoferrin is usually significantly increased in IBD, but it can also increase with infective diarrhea, colon cancer, and after taking NSAIDS (14).  Like calprotectin, lactoferrin may also be useful in monitoring the treatment one is receiving for IBD.  And since lactoferrin is usually negative in IBS, this marker can also help to differentiate IBD from IBS (15).

Reference range: Doctor’s Data uses a reference range of less than 7.3 mcg/mL

Secretory IgA.  Secretory IgA (SIgA) is found on the mucosal surfaces of the body, and it plays an important role in providing protection by separating the outside environment from the inside of the body (16).  This is a process called immune exclusion, as it limits the entry of pathogens and antigens (16).  As a result, it is common for there to be elevated levels of secretory IgA in the presence of an infection, and sometimes a food allergen.  There is also evidence of elevated secretory IgA levels in inflammatory bowel disease (17), although it seems as if calprotectin and lactoferrin are better markers.  On the other hand, chronic stress can result in a decrease in SIgA, which in turn can increase one’s susceptibility of having an infection or an increase in intestinal permeability (18).

Reference range: The reference range seems to depend on the lab, as Doctor’s Data uses a reference range of 51-204 mg/dL, while Genova Diagnostics uses a range less than 885, with the units not specified.

Lysozyme.  Lysozyme is an enzyme that is secreted at the site of inflammation in the gastrointestinal tract.  Lysozyme levels also seem to be elevated in people with IBD (19).  One study showed that neutrophils cause elevated fecal lysozyme levels in ulcerative colitis and macrophages cause elevated serum lysozyme levels in Crohn’s disease (20).

Reference range: The labs I’m familiar with use a reference range of less than 600 ng/mL

Eosinophilic Protein X.  There is evidence that eosinophils are involved in the pathophysiology of numerous inflammatory conditions of the gut.  Eosinophils contain different proteins which are cytotoxic, and are released from the eosinophils after being activated.  One of these proteins includes eosinophil protein X (EPX).  Some suggest that EPX might be a better marker of low grade inflammation, whereas other markers such as calprotectin and lactoferrin usually don’t test positive until someone has a significant amount of intestinal inflammation.  A few studies show that EPX is positive in inflammatory bowel disease (21) (22) (23).

Reference range: Genova Diagnostics is the only lab I know of which tests for this, and they use a reference range of less than 4.6 mcg/g

Autoantibodies.  Although autoantibodies aren’t considered to be inflammatory markers, the presence of elevated autoantibodies usually correlate with an inflammatory process.  In other words, when someone has elevated autoantibodies, inflammation will also be present.  There are many different autoantibodies one can test for, but with regards to thyroid autoimmunity, the most common ones include thyroid peroxidase antibodies, thyroglobulin antibodies, and thyroid stimulating immunoglobulins.   The first two autoantibodies I mentioned are associated with Hashimoto’s Thyroiditis, while thyroid stimulating immunoglobulins are commonly found in patients with Graves’ Disease.

Reference range: These are common reference ranges for the following thyroid antibodies:

Thyroglobulin antibodies: 0-0.9 IU/mL

Thyroid peroxidase (TPO) antibodies: 0-34 IU/mL

Thyroid stimulating immunoglobulins (TSI): <140%

Proinflammatory Cytokines.  Autoimmunity involves the presence of proinflammatory cytokines, and although I don’t test the cytokines in my patients, some doctors do.  Some examples of proinflammatory cytokines that can be tested include Interleukin-1 beta (IL-1β, Interleukin-6 (IL-6), Interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α).

Which Inflammatory Markers Should You Test For?

I have most of my patients test for hs-CRP through the blood.  I don’t always test for ESR, although some healthcare professionals will test hs-CRP and ESR on all of their patients.  I do test for the thyroid antibodies in my patients.  As I mentioned earlier, I don’t do testing for cytokines.  As for calprotectin, lactoferrin, lysozyme, and some of the other stool markers, there are times when I will do stool testing on my patients, although it’s not something I do with every patient.  If someone is having a lot of gut issues and/or symptoms of inflammatory bowel disease then obtaining a stool panel might be a good idea.  However, there are functional medicine doctors who will recommend a comprehensive stool panel with every single one of their patients, and especially those with autoimmune thyroid conditions.

In summary, inflammation is a factor with just about every autoimmune condition, including Graves’ Disease and Hashimoto’s Thyroiditis.  Some of the different inflammatory markers include C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), calprotectin, lactoferrin, lysozyme, secretory IgA, Eosinophilic Protein X, and proinflammatory cytokines.  Although autoantibodies aren’t considered to be an inflammatory marker, if an autoimmune thyroid condition is suspected then it makes sense to test the thyroid antibodies.  In addition to testing the thyroid antibodies, I commonly test for hs-CRP, and while I don’t do testing for cytokines, there are times when I will recommend testing for one or more of the other inflammatory markers.