Many people are aware of the importance of healthy vitamin D levels with regards to bone health.  But vitamin D has many other important functions.  In fact, just about every tissue and cell in your body has vitamin D receptors.  Unfortunately, many people are deficient in vitamin D.  Others fall within the recommended lab reference range, but while most of the research still suggests that optimal levels should be above 30 ng/mL, some sources, including the vitamin D Council, suggest for these levels to be greater than 50 ng/mL.

I’d like to start out by discussing the mechanism of action of vitamin D.  This can get pretty complex, and so I’m just going to cover the basics.  Although vitamin D is referred to as a vitamin, the active form is actually a prohormone, and this is produced in the skin through the ultraviolet irradiation of 7-dehydrocholesterol, which is a cholesterol precursor.  So 7-dehydrocholesterol is converted into vitamin D3 (also known as cholecalciferol) in the skin.  However, vitamin D3 is biologically inert, and it needs to be metabolized to 25-hydroxy vitamin D3 in the liver, and then it gets metabolized to 1, 25 hydroxy vitamin D3 (also known as calcitriol) in the kidneys by the enzyme CYP27B1, although other tissues have this enzyme as well.

More Facts About Vitamin D

Vitamin D and its metabolites are carried in the blood mostly bound to vitamin D binding protein (DBP) (1).  So what happens is that after cholecalciferol (vitamin D3) is manufactured or taken as a supplement, it binds to DBP, and after it gets converted into calcitriol, this also is carried through the blood by DBP before binding to the vitamin D receptor.

Vitamin D increases the intestinal absorption of calcium and phosphorus, which in turn promotes bone mineralization and remodeling, and it is also involved in regulating serum calcium and phosphorus levels.  This is the main reason why most medical doctors test for Vitamin D, as they are concerned about low levels affecting bone mineral density.  However, vitamin D has numerous other functions, as it also plays a role in neuromuscular function and influences cellular growth and differentiation.  It also plays a big role in immunity, which of course is important for those with autoimmune thyroid conditions such as Graves’ Disease and Hashimoto’s Thyroiditis.  I’ll talk more about this later.

What’s The Difference Between Vitamin D2 and D3?

Supplemental vitamin D comes in two primary forms.  When someone purchases vitamin D in a health food store they are usually getting cholecalciferol, which is also known as vitamin D3.  On the other hand, when a medical doctor writes a prescription it is for ergocalciferol, which is known as vitamin D2.  Even though some sources claim that these two are equivalent, vitamin D3 has been proven to be the more potent form of vitamin D in all primate species, including humans (2).  In addition to vitamin D3 being more effective than vitamin D3, there is diminished binding of vitamin D2 metabolites to vitamin D binding protein in the plasma, a nonphysiologic metabolism, and a shorter shelf life of vitamin D2 (2).

Vitamin D and The Research                           

What I’d like to do now is discuss some of the research involving vitamin D, including numerous conditions which are affected by a vitamin D deficiency.

Vitamin D in dementia and cognition.  A few studies show that a vitamin D deficiency can increase one’s risk of dementia, and even Alzheimer’s disease (3) (4) (5).  Vitamin D receptors are abundant in the tissues of the brain, and the active form of vitamin D has neuroprotective effects which include the clearance of amyloid plaques, which is a hallmark of Alzheimer’s disease (6).

Inflammation/autoimmunity.  There are also numerous studies which show that vitamin D plays an important role in modulating the immune system and inflammation (7) (8) (9).  It appears to do this by decreasing pro-inflammatory cytokines, and is also associated with higher regulatory T cells (10) (11), which help to suppress autoimmunity.  However, some sources question whether a vitamin D deficiency is a cause of inflammation, or if it is a consequence of the inflammatory process (12) (13).

High Blood Pressure/Cardiovascular disease.  Numerous studies show that vitamin D might have antihypertensive effects in those people with essential hypertension, which in turn can help to prevent the development of a stroke (14) (15).  There is also evidence that a vitamin D deficiency can be a risk for the development of peripheral arterial disease (16) (17).  Although there is some evidence linking a vitamin D deficiency to atherosclerosis (18), other studies suggest that more research is needed in this area (19).

Osteoporosis.  One of the main functions of the active form of vitamin D is to enhance the intestinal absorption of calcium.  And this is why healthy vitamin D levels are important for healthy bone mineral density (20) (21).

Gut microbiota/Intestinal mucosal barrier.  There is evidence that vitamin D may play an important role in gut homeostasis and in the signaling between the microbiota and the host (22).  In addition, the vitamin D receptor appears to play a critical role in homeostasis of the intestinal mucosal barrier by preserving the integrity of the junction complexes (23).

Cancer.  Since vitamin D is important for optimal immune system health then it shouldn’t be surprising that some studies show that intake or synthesis of vitamin D leads to the reduced incidence and death rates of colon, breast, prostate, and ovarian cancers (24) (25) (26) (27).

Thyroid Health.  Numerous studies show a correlation between vitamin D deficiency and autoimmune thyroid disease.  A few studies have shown that low levels of vitamin D is associated with the presence of antithyroid antibodies and abnormal thyroid function (28) (29).  Both people with Hashimoto’s Thyroiditis and Graves’ Disease commonly have low levels of vitamin D (30) (31) (32).  This doesn’t mean that a vitamin D deficiency is the cause of these conditions, although having such a deficiency might make someone more susceptible to developing thyroid autoimmunity.

Autism.  There is evidence that healthy levels of vitamin D might reduce the risk of autism (33).  In addition, supplementation of vitamin D (in those who are deficient) may significantly improve the outcome of some children with Autism Spectrum Disorder through its anti-inflammatory actions, antiautoimmune effects, increasing regulatory T cells, protecting the mitochondria, and upregulating glutathione (33) (34) (35).

Infections.  Since healthy vitamin D levels are necessary for a healthy immune system, it makes sense that a vitamin D deficiency can increase one’s risk of developing infections.  There is some evidence that it can reduce the incidence of influenza (the flu), and one study suggests keeping the levels around 50 ng/mL to prevent infection (36) (37) (38).

In the next blog post I will start out by talking about why many people are deficient in vitamin D.  I will also talk about how to test the vitamin D levels, as while most healthcare professionals test for 25-OH vitamin D, since 1,25-OH vitamin D is the active form, I’m sure that some people reading this are wondering if this should be tested.  I will also discuss three ways to increase vitamin D levels.

Hashimoto’s Thyroiditis is an autoimmune thyroid condition that is characterized by elevated thyroid autoantibodies.  An encephalopathy is general term for a disease of the brain.  Hashimoto’s encephalopathy is an autoimmune condition that not only involves elevated thyroid antibodies, but it also is characterized by brain dysfunction.  In fact, the encephalopathy symptoms are usually more prominent than the thyroid symptoms.  While Hashimoto’s Thyroiditis is common, Hashimoto’s encephalopathy is a rare condition.

Because there are thyroid autoantibodies present in Hashimoto’s encephalopathy, not surprisingly one can have thyroid hormone imbalances.  This can lead to the classic hypothyroid symptoms such as fatigue, weight gain, cold hands and feet, etc.  However, many times the person with Hashimoto’s encephalopathy is in a subclinical hypothyroid state, and so while they might have elevated thyroid antibodies, they frequently will present with a normal thyroid panel and minimal hypothyroid symptoms.  As I’ll discuss below, other autoantibodies are present as well, which can lead to psychiatric manifestations, seizures and focal neurologic deficits (1).

The Autoantibodies Associated With Hashimoto’s Encephalopathy

Hashimoto’s encephalopathy involves numerous autoantibodies.  These can include elevated thyroglobulin antibodies, thyroid peroxidase antibodies, or both.  These thyroid antibodies are of course commonly seen in Hashimoto’s Thyroiditis.  But with Hashimoto’s encephalopathy, in addition to one or both thyroid autoantibodies being present, there are also autoantibodies against alpha-enolase (2) (3) (4).

Alpha-enolase, also known as Enolase 1, is a glycolytic enzyme.  These autoantibodies are found in other autoimmune conditions as well, such as Behçet’s disease (5).  Enolase exists in three different forms: α, β and γ (4). Isozyme α is found in most tissues, isozyme β in muscle, and isozyme γ is present mainly in nervous tissue (5) (6). It appears that the antibodies in Hashimoto’s Encephalopathy only involve α-enolase (4).

What’s important to understand here is that autoimmunity involves the body attacking its own cells and tissues.  What differentiates one autoimmune condition from another is that different parts of the body are attacked.  So with Hashimoto’s the immune system will attack either thyroglobulin, or the thyroid peroxidase enzymes, which is why you will see one or both of these antibodies elevated.  With Hashimoto’s encephalopathy you will not only see an increase in one or both of these thyroid antibodies, but since the immune system is attacking alpha-enolase, you will see elevated levels of these autoantibodies as well.  As for why one person will develop Hashimoto’s Thyroiditis, while another person will develop Hashimoto’s encephalopathy, it comes down to a combination of genetics, lifestyle factors, and environmental triggers.

What Is The Conventional Treatment Approach?

Corticosteroids are commonly recommended as the first line of treatment in those people with Hashimoto’s encephalopathy (7) (8).  And while many people respond very well to corticosteroids, several adverse outcomes, relapses and temporary or permanent spontaneous remissions have also been reported (8).  This doesn’t mean that I’m opposed to people using corticosteroids, as while I’m not a big fan of them, I realize that in some cases they might be necessary to take.  There have also been a few case studies where intravenous immunoglobulins were beneficial (9) (10), as they help by modulating the immune system.

Can A Natural Treatment Approach Help?            

Although conventional medical treatments might be necessary at times to help manage the symptoms, and possibly to help put the person into a state of remission, what we of course need to keep in mind is that treatments such as corticosteroids and intravenous immunoglobulins are not addressing the cause of the problem.  As a result, even if the person is put into a state of remission through modulation of the immune system, relapses are common.  This was highlighted in a case report I came across that involved a 43-year old woman with Hashimoto’s encephalopathy who experienced three relapses around the time of her menstrual cycle (11).

After the third relapse she was given thyroid hormone medication for her hypothyroidism, and she was also given estrogen and progesterone to help regulate her menstrual cycle.  After this she didn’t experience any further relapses.  If she were my patient I might have tried to address her problem without giving estrogen and progesterone, but the point I want to get across is that the apparent trigger was addressed in this situation.  Unfortunately, addressing the cause of the problem isn’t always this straightforward, but either way, one does want to ideally detect and address the cause of the problem.  So if someone has a hormone imbalance, infection, food sensitivity, toxic exposure, or another factor that is triggering the autoimmune response then of course this needs to be addressed.

You might wonder if natural agents can be used instead of corticosteroids and intravenous immunoglobulins.  In some people nutritional supplements and herbs can be used to help suppress the autoimmune response, although the cause of the problem still needs to be addressed.  But taking things that can reduce proinflammatory cytokines and increase regulatory T cells can help, including fish oils, vitamin D, curcumin, and resveratrol.  I’ve discussed this in greater detail in other articles and blog posts, and keep in mind that high doses might be necessary to help suppress the autoimmune component.

In summary, Hashimoto’s encephalopathy is an autoimmune condition that not only involves elevated thyroid antibodies, but it also is characterized by having autoantibodies against alpha-enolase.  This in turn can lead to symptoms of brain dysfunction, including psychiatric manifestations, seizures, and focal neurologic deficits.  Corticosteroids and intravenous immunoglobulins are two types of conventional treatments, with corticosteroids usually the first option.  Natural treatments might also help to put the person into remission, but whether you use natural or conventional methods to control the symptoms, the ultimate goal should be to address and remove the autoimmune trigger.

When I was dealing with Graves’ Disease I chose not to take any medication.  I decided not to take the beta blocker that was prescribed by the primary care physician who told me I had hyperthyroidism, and then I refused to take the Methimazole that was recommended by the endocrinologist who diagnosed me with Graves’ Disease.  It was approximately two months between these two doctor visits, and I didn’t begin taking bugleweed (and eventually motherwort) until after my appointment with the endocrinologist.  While everything turned out okay, I was taking a big risk by not managing my hyperthyroid symptoms for so long, and I decided to put this blog post together because unmanaged hyperthyroidism has numerous risks, and I’m going to discuss three of the main ones here.

Getting back to my situation, if the bugleweed and motherwort didn’t do a good job of managing my symptoms then I’m pretty sure I would have taken the antithyroid medication while trying to restore my health.  While it might sound hypocritical telling people with hyperthyroidism the risks of not managing their symptoms when this is exactly what I did for a couple of months, keep in mind that at the time I wasn’t working with other people who had hyperthyroidism and Graves’ Disease.  If I knew then what I know now about hyperthyroidism and Graves’ Disease I wouldn’t have gone so long without managing my symptoms.

With that being said, let’s go ahead and take a look at three of the main risks of unmanaged hyperthyroidism:

Risk #1: Decrease in bone density.  Thyroid hormones are required for skeletal development and establishment of peak bone mass (1).  In adults, T3 regulates bone turnover and bone mineral density, and normal levels of thyroid hormone are essential to maintain optimal bone strength (1).  Overt hyperthyroidism can cause accelerated bone remodeling, reduced bone density, osteoporosis, and an increase in fracture rate (2) (3).  Although this decrease in bone density is reversible (3) (4), it can take years to reverse osteopenia and osteoporosis.

In order to avoid a decrease in bone density it is important to address elevated thyroid hormone levels.  This can be accomplished through antithyroid medication such as Methimazole or PTU, or in many cases by taking an antithyroid herb such as bugleweed.  Just keep in mind that not everyone is able to lower their thyroid hormone levels by taking bugleweed, and when this is the case then it might be necessary to take antithyroid medication.  In addition to lowering the thyroid hormone levels, eating a healthy diet and engaging in some weight-bearing exercises at least a few days per week can also help to increase the bone density.

Risk #2: Thyroid storm.  A thyroid storm is a rare complication of hyperthyroidism, and is frequently caused by a secondary event such as an infection or myocardial infarction (5).  In addition to the person presenting with elevated thyroid hormone levels, they usually will have an extremely high heart rate (i.e. greater than 140 beats per minute), and a fever greater than 102 degrees Fahrenheit (>39 degrees Celsius) is almost universal (5).  Other symptoms can include persistent sweating, shaking, diarrhea, nausea, vomiting, and disorientation. The overall mortality of a thyroid storm is between 10-20% (5) (6), and this assumes that there is no delay in treatment.  This is considered to be a medical emergency, and so if you are experiencing some of the symptoms I just described then you need to take this seriously, and it probably would be wise to visit the nearest urgent care or hospital emergency center.

3) Atrial fibrillation.  An atrial fibrillation is the most common type of heart arrhythmia, and this involves an abnormal heart rate and/or heart rhythm.  Atrial fibrillation is the most common cardiac complication of hyperthyroidism, and it can increase the risk of blood clot formation inside the heart (7).  The best way for someone with hyperthyroidism to prevent atrial fibrillation from occurring is to make sure their resting heart rate isn’t too high.  I discussed this condition in greater detail in an article I wrote entitled “Hyperthyroidism and Atrial Fibrillation“.

Should You Take Medication or Herbs To Manage The Hyperthyroid Symptoms?

Some people have a difficult time deciding whether they should take antithyroid medication to manage their symptoms, or if they should choose to do this naturally through herbs such as bugleweed and motherwort.  Although I personally chose not to take the medication, some people aren’t able to effectively manage their symptoms through herbs alone.  And if this is the case, then taking medication on a temporary basis is probably a good idea.  After all, while it’s great if you can manage your symptoms naturally, even if you do need to take antithyroid medication you can still follow a natural treatment protocol.  In fact, it’s quite common for patients with hyperthyroidism to already be on antithyroid medication prior to working with me.  If you’re still not sure what to do, I would check out the following blog post I wrote entitled ” Choosing Between Prescription Drugs and Natural Supplements In Managing The Hyperthyroid Symptoms“.

In summary, while many people with hyperthyroidism and Graves’ Disease can benefit from following a natural treatment protocol, it is important to manage the symptoms while taking this approach.  There are risks of unmanaged hyperthyroidism, and three of the main risks include a decrease in bone density, thyroid storm, and atrial fibrillation.  The incidence of these three conditions can be greatly reduced by decreasing the thyroid hormone levels through the use of antithyroid medication such as Methimazole, or herbs like bugleweed.  And if you have an elevated resting heart rate then of course you also want to take action to help lower this.  Frequently the antithyroid medication or herbs will help to accomplish this, although sometimes taking an agent that specifically focuses on the cardiac symptoms is necessary, and is why some people will take a beta blocker or an herb such as motherwort.

Many people have low levels of the hormones DHEA, testosterone, estrogen, and progesterone.  And while there are numerous factors which can cause low levels of these hormones, one of the biggest factors that can cause this is something known as the pregnenolone steal, also referred to as the cortisol steal.  Many doctors will recommend bioidentical hormones to correct hormone deficiencies, and while there is a time and place for hormone replacement, it of course is preferable to correct the cause of the problem whenever this is possible.  And so in this post I’m going to discuss what the pregnenolone steal is, how it can lead to deficiencies in other hormones, and what you can do to correct this problem.

I’ve spoken about the hormone pathway in some past articles and posts, but I’m going to give a little refresher here.  First of all, it’s important to understand that all of the steroid and sex hormones are derived from cholesterol.   In other words, if you have very low cholesterol levels then this alone can result in low hormone levels.  And the reason I need to emphasize this is because many medical doctors prescribe statins to a lot of their patients, and these statins can result in low cholesterol levels.  So while you don’t want cholesterol levels that are extremely high, you also don’t want to have very low cholesterol levels.

So the hormone pathway starts with cholesterol, and the hormone pregnenolone is synthesized from cholesterol.  This takes place in the mitochondria, and so if someone has mitochondrial dysfunction then this can affect the production of pregnenolone.  But assuming this isn’t the case, pregnenolone can convert into either progesterone or DHEA, and these in turn convert into other hormones.  Let’s take a look at each of these pathways:

Conversion of Pregnenolone Into DHEA.  Pregnenolone gets converted into 17-hydroxy pregnenolone by the enzyme 17α-hydroxylase.  17-hydroxy pregnenolone will in turn get converted into dehydroepiandrosterone (DHEA) by the enzyme 17,20 lyase.  DHEA is the precursor of androstenedione, which in turn is a precursor of testosterone.  Testosterone in turn can convert into estradiol via the enzyme aromatase, and dihydrotestosterone (DHT) via the enzyme 5α-reductase.

Conversion of Pregnenolone into Progesterone.   Pregnenolone converts into progesterone, which in turn gets converted into 17-hydroxy progesterone by the 17α-hydroxylase enzyme.  17-hydroxy progesterone will in turn be converted into 11-deoxycortisol, which in turn is converted into cortisol by the enzyme 11beta-hydroxylase.  17-hydroxy progesterone can also convert into androstenedione, with the help of the enzyme 17,20 lyase.  So progesterone ultimately leads to the formation of cortisol, although it can also lead to the formation of androstenedione.  Progesterone can also be converted into aldosterone, which takes place in multiple steps.

What Is The Pregnenolone Steal?

The pregnenolone steal is what happens when someone deals with prolonged chronic stress.  Out of all of the hormones I listed above, the production of cortisol is a priority.  And if someone is in a stressed out state, cortisol will be produced at the expense of DHEA.  So with the hormone pathway I discussed, you’ll recall that pregnenolone can be converted into both progesterone and DHEA, which in turn will convert into the other hormones I mentioned.  If someone is stressed out then this will inhibit the enzyme 17,20 lyase, which  helps to convert 17-OH pregnenolone into DHEA, and 17-OH progesterone into androstenedione.

So what is the consequence of this?  Well, if these enzymes are inhibited then this will result in a decrease of DHEA and androstenedione.  And remember that these hormones are precursors to testosterone, and this hormone converts into estradiol and DHT.  As a result, the pregnenolone steal can result in decreased levels of DHEA, androstenedione, testosterone, estradiol, and DHT.  Keep in mind that not all of these hormones will instantaneously become depleted, and so initially you might see some of these hormones depressed, while other hormones will look fine.

So the pathway that converts pregnenolone into progesterone will predominate.  However, cortisol is a priority over progesterone, and so progesterone will also decrease in order to produce more cortisol.  This is why this process is also referred to as the “cortisol steal” by some sources.

How Can The Pregnenolone Steal Be Diagnosed?

Sometimes it can be challenging to tell if someone is going through the pregnenolone steal, but in most cases you will see elevated cortisol levels, followed by low levels of one or more of the sex hormones.  If cortisol is high and all of the sex hormones are low or depressed, then you can be confident that the pregnenolone steal is a factor.  But wait, if someone is in postmenopause, isn’t it normal for the sex hormones to be depressed?  In other words, is it possible that if all of the sex hormones are low it’s simply due to the aging process?

Well, without question the hormones do decrease as we age.  However, this doesn’t mean that they should be depressed.  And if cortisol is elevated, then this is a pretty good sign that the pregnenolone steal is at least part of the problem.  Sure, there can always be other factors, such as one’s age, but if chronic stress is a factor then this needs to be addressed.

What are some of the symptoms someone will experience during the pregnenolone steal?  Since this involves high cortisol and low sex hormones, then the symptoms will usually correlate with this.  So for example, if someone is experiencing hot flashes or a low libido, then this probably is due to a deficiency of one or more of the sex hormones.  Other symptoms can include menstrual irregularities, anxiety or depression, vaginal dryness, insomnia, irritability, fatigue, and numerous other symptoms.  So when someone has one or more of these symptoms then it’s possible that the pregnenolone steal is the root cause of the problem.

How Can You Reverse The Pregnenolone Steal?

As for how you can halt and reverse this process, the two most important things you can do is to 1) reduce the stress in your life, and 2) improve your stress handling skills.  I realize that sometimes people can’t reduce their stress levels, but either way it is important to work on stress management.  Remember that chronic stress will inhibit the enzymes which lead to the production of DHEA, along with the androgens and estrogens.  And so if you don’t do anything to improve your stress handling skills,  then your body will continue to produce cortisol at the expense of your sex hormones.

So you need to block out time to manage the stress in your life.  I personally use a biofeedback program by the company Heart Math, as I block out 12 to 15 minutes each night before I go to bed.  Sure, I probably should be doing more than this, but it’s definitely better than nothing.  And in my opinion it’s better to spend 10 to 15 minutes EVERY DAY on stress management than 30 minutes three times per week.  Of course you don’t need to use Heart Math, as many people improve their stress handling skills through techniques such as yoga and meditation.  And there are other mind body medicine techniques as well.  I talk more about this in my article entitled “Mind Body Medicine and Thyroid Health“.

In summary, the pregnenolone steal occurs when someone is in a stressed out state.  When this is the case the body will do everything it can to produce cortisol, which in turn will inhibit the enzymes that lead to the formation of the androgens and estrogens.  So if someone has elevated cortisol levels and low sex hormones, then this is an indication that the pregnenolone steal is occurring.  And in order to halt this process you need to reduce your stress levels and improve your stress handling skills.  Some ways to accomplish this is through yoga, meditation, and biofeedback.

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.