Do you believe your thyroid isn’t working properly but your doctor says your tests are fine?

Do you have low energy levels or an inability to lose weight but you’re told it’s all in your head?

The truth is, your thyroid may be working fine but that doesn’t mean there isn’t a problem with thyroid signaling.

Nonthyroidal illness syndrome(NTIS), also known as euthyroid sick syndrome, is a condition where active thyroid hormone(T3) levels are low even though tests for thyroid function are normal(1).  Your doctor will test your thyroid function by measuring thyroid stimulating hormone(TSH) and thyroxine(T4) levels.

What the tests show…

Taken from: http://alaskahealth.info/thyroid-hormones-thyroid-tests/

Under normal operating conditions, the hypothalamus secretes thyrotropin releasing hormone(TRH) which signals the pituitary to release TSH.  TSH stimulates the thyroid to produce T4, the inactive form of thyroid hormone, and T3.

Most thyroid hormone produced by the thyroid is T4 which circulates and gets converted to T3 in tissues.  The liver is a major player in the conversion of T4 to T3 and excess circulating levels feed back to the hypothalamus and pituitary to shut off TRH and TSH.

When TSH levels are high, this shows that the thyroid isn’t producing enough T4 and T3.   This indicates thyroid dysfunction because T4 and T3 aren’t making it back to the hypothalamus and the pituitary to shut off TSH production.

Low T4 levels imply that the thyroid hormone isn’t producing enough thyroid hormones.  But, in NTIS, T4 levels can be normal because the problem isn’t with the thyroids ability to produce thyroid hormone(1).  The problem is disruption of thyroid hormone signaling somewhere in the body.

This doesn’t mean thyroid output is correct, it just means that the thyroid makes thyroid hormone just fine.  Think of it this way.  You may be an awesome architect and I may be an awesome builder, but if we don’t communicate properly we could build a crappy house.

NTIS can present in the following ways:

1. Low TSH, Normal T4
2. Normal TSH, Normal T4
3. Low TSH, low T4
4. Normal TSH, low T4

Keep in mind that normal and low TSH are considered ok, while high TSH is indicative of a problem.  Typically, NTIS starts with normal TSH with no effect on T4 levels.  As it progresses, T4 levels drop and T3 levels follow.  Reverse T3(rT3) increases, which can block T3 from binding to receptors(1).

The cumulative effect here is a reduction in cellular energy due to poor T3 activity.  This is a result of both low T3 production/conversion and an inability of T3 to bind to receptors to carry out its role in generating cellular energy.

Causes of NTIS

NTIS can occur in a few situations.  First and foremost, starvation induces this response because of low energy intake(1).  It makes sense, if you aren’t eating enough energy you need to conserve it.  Without this, death due to starvation would occur much earlier.

Carbohydrate deprivation also causes NTIS.  For reasons that aren’t quite known, proper thyroid signaling is dependent on adequate carbohydrate intake(1).  Lower carbohydrate intake typically means higher fat intake which could also be the ultimate cause of the issue.

Surgery can also cause NTIS.  Specific surgeries include bypass and bone marrow transplant but most surgeries can induce this syndrome(1).

The final cause of NTIS indicates what may be the most common way an otherwise healthy person develops it.  Sepsis, a system-wide inflammatory response to infection, is a primary cause of NTIS(1).

What is sepsis?

Lipopolysaccharide(LPS) is a component of the cell wall of gram negative bacteria that causes an inflammatory response.  When bacteria that contain LPS leak from the gut in to the circulation, sepsis occurs.  This is one of the primary reasons a “leaky gut” can cause so many problems.

Sepsis is a common cause of death, but it appears that sepsis isn’t an “either you have it or you don’t” type of thing.  As it turns out, low grade sepsis is very common and also called low grade endotoxemia.

People with cardiovascular disease(2), type 2 diabetes(3), and obesity(2, 3) have higher circulating levels of LPS than healthy people.  This induces a state of chronic inflammation.

Even healthy people have LPS in their gut and blood, they just have levels that are much lower than individuals with chronic inflammatory disease.  This is due to a stronger intestinal barrier preventing LPS from getting in and a more robust immune response that prevents it from accumulating in the blood.

The immune response to LPS changes signaling everywhere in the body.  It affects blood glucose regulation, hormonal balance, the cardiovascular system, and changes energy metabolism.  LPS causes many issues that disrupt thyroid hormone signaling so it’s important to understand the process of low grade endotoxemia. For a more comprehensive review of this process, check this blog out

Another important consideration is that LPS has effects on thyroid hormone signaling outside of the effects of inflammation.  Injecting inflammatory cytokines has a much smaller effect on thyroid function than injecting LPS(4).

Anyone wishing to improve the way their thyroid and thyroid hormones work needs to be aware of the way LPS affects thyroid signaling.  A lot is made of the relationship between inflammation and autoimmune thyroiditis, but the signaling effects of LPS can pose problems without a smoking gun clinical diagnosis.

Now that we have that out of the way, let’s get cracking on the 6 ways the gut affects thyroid signaling.

1)LPS induced inflammation in the thyroid can lead to hyperthyroidism

As mentioned above, LPS is a component of the cell wall of bacteria that drives up inflammation.  In order to identify bacteria, most cells in the human body contain toll-like receptors that recognize bacterial cell components and induce inflammation.

Toll-like receptor 4(TLR4) specifically recognizes LPS and causes inflammation through nuclear-factor kappa beta(NF-kB).  NF-kB is one of the major regulators of inflammation in the body, but plays another key role in thyroid function.

Taken from: http://classes.midlandstech.edu/carterp/Courses/bio211/chap16/chap16.htm

Thyroid hormone is basically made up of tyrosine and iodine.  Thyroglobulin is a long chain of tyrosine molecules that bind with iodine to form the thyroid hormones.  T4 contains 4 iodine molecules while T3 contains only 3.

NF-kB increases this process.  LPS binds to toll-like receptor 4(TLR4) on thyroid cells and activates NF-kB.  NF-kB increases iodine uptake in the thyroid and increases thyroglobulin production(4).  This combined effect increases thyroid hormone production and may be responsible for hyperthyroidism.

Layman’s breakdown: A key protein in the inflammatory process also plays a role in regulating the amount of iodine the thyroid absorbs from the bloodstream.  When there is inflammation, the thyroid absorbs more iodine and makes more thyroglobuin.   These are the 2 key components of thyroid hormone and this process can lead to hyperthyroidism.

2)LPS inhibits type 1 deiodinase in the liver

Taken from: http://www.medscape.com/viewarticle/722086_8

The thyroid gland only puts out about 20% of active T3 in the blood.  The remaining 80% comes from converting the inactive T4 to T3 in peripheral tissues such as muscle and the liver(5).  This conversion is carried out by deiodinases which remove an iodine from T4 to make it T3.

Type 1 deiodinase converts the inactive form of thyroid hormone(T4) to its active form(T3) in the liver.  The conversion of T4 to T3 in the liver is one of the major sources of T3 in the blood(5).  LPS inhibits this process and can have a substantial effect on serum T3 levels.

Layman’s breakdown: Most of the thyroid hormone secreted by the thyroid is in its inactive form T4.  In order for it to become active, an iodine molecule needs to be removed to make T3.  Deiodinases in tissues outside the thyroid perform this process. 

LPS binds to deiodinase 1 in the liver and blocks it from converting T4 to T3.  This lowers energy production and the livers contribution to blood levels of T3.

3)LPS induces Type 2 deiodinase in the hypothalamus and pituitary

As mentioned above, the hypothalamus and pituitary gland play a large role in regulating thyroid hormone levels.  LPS interferes with this signaling by increasing type 2 deiodinase activity in the hypothalamus(5).  This actually increases the conversion of T4 to T3, but has the additional effect of shutting off TRH/TSH secretion and lowering thyroid output

This may suppress TSH production and present as if there’s no thyroid problem on a standard TSH test.  The problem is that the signal in the brain isn’t an accurate picture of whole body T3 levels because TSH and possibly even T4 are normal

Looking at T3 and T4 gives a better picture and shows both to be low.  This may be how many thyroid problems go unidentified due to only testing TSH.

Layman’s breakdown: While LPS lowers the conversion of T4 to active T3 in the liver, it actually increases it in the hypothalamus.  The hypothalamus plays a primary role in regulating thyroid hormone output by stimulating TSH production. 

By increasing the amount of T3 in the hypothalamus, this tells the thyroid gland that it’s making enough thyroid hormone.  However, since LPS is also blocking T4 to T3 conversion in the liver, your level of active T3 is actually below normal.  This would make you feel low energy despite having normal TSH/T4 levels.

4)Serum bile acids promote type 2 deiodinase activity in muscle and brown fat

Taken from: http://www.nature.com/nrgastro/journal/v11/n1/fig_tab/nrgastro.2013.151_F2.html

Bile acids are mostly contained in the gut but some do enter the circulation via the portal vein.  This distributes a small amount of bile acids to peripheral tissues.

Bile acids bind to the TGR5 bile receptor in brown fat and skeletal muscle.  This increases type 2 deiodinase activity in these tissues and leads to an increase in T3(6, 7).  The overall effect is increased energy expenditure in both tissues and may contribute to serum T3 levels.

People with poor bile output may have low T3 levels due to this effect.  In addition when bile acids bind to TGR5, they reduce the inflammatory response to LPS.

Layman’s breakdown: Bile is produced in the liver and secreted in to the gut.  Some of the bile acids enter the bloodstream and have an effect on other tissues such as muscle cells and brown fat cells. 

When bile acids bind to receptors on these cells, it increases the conversion of T4 to T3.  This improves local energy production in these cells and contributes to total body T3 levels.

Bile acids also have an anti-inflammatory effect in these same tissues.  Since they specifically reduce the inflammatory response to LPS, they can at least partially resolve the negative effect of LPS on these tissues. 

It’s important to realize that there is always going to be LPS in your bloodstream whether you are healthy or not.  We just want to make sure that the processes that reduce its negative effects are working properly.

5)Thyroid hormones participate in the enterohepatic circulation

Another problem with poor bile output is that thyroid hormones get conjugated in the liver and enter the enterohepatic circulation for disposal. This is to make them water soluble so they can be removed via feces or urine..

Thyroid hormones get conjugated via sulfation or glucuronidation.  The gut as well as bacteria in the gut contain enzymes that deconjugate thyroid hormones and allow them to re-enter the circulation.  T4- and T3-sulfate are believed to play a major role as a back up sink for thyroid hormones(5).

We don’t know how much gets recirculated.  A study looking at rats showed that feeding them T4 and T3 led to the recirculation of 43% and 34% of the hormones from the gut in to the blood, respectively(9).  This indicates that the enterhpatic circulation of T4 and T3 may be pretty substantial.

With insufficient bile, T4 excretion decreases while serum T4 levels rise(8).  Since excess T4 gets converted to reverse T3 and reverse T3 antagonizes regular T3, this negatively impacts thyroid hormone signaling in tissues throughout the body.

Layman’s breakdown: There is a circulation between your liver and gut called the enterohepatic circulation(EHC).  When the liver is disposing of excess hormones, toxins, and other fat soluble molecules, it conjugates them to make them more easily dissolve in water so they can be dumped. 

T4 and T3 are 2 hormones that the liver does this with.  As these hormones travel through the gut, bacteria deconjugate them and they can be absorbed again so they may play a role in total body hormone levels.

The role of bile here is two-fold.  Since the thyroid hormones are dumped in to bile by the liver, interrupted bile flow can cause an accumulation of T4 in the blood.  Excess T4 is converted in to something called reverse T3 which binds to the same receptors as regular T3 but doesn’t increase metabolism.  So it basically blocks the effects of T3. 

Bile acids are also needed to reabsorb T4 and T3 sulfate so low bile acids can lower blood levels of T4 and T3.   This process may contribute a large amount of thyroid hormones to the blood.

6)LPS impairs thyroid hormone and retinoid x receptor expression in the liver

Taken from: http://www.nature.com/nrendo/journal/v10/n10/full/nrendo.2014.143.html

When thyroid hormone enters cells, it binds to the thyroid hormone receptor(THR) and travels to the nucleus to change gene expression.  This is how thyroid hormone exerts its effect on cellular energy metabolism.

Although the THR can function on its own when T3 binds to it, it functions best when it binds with the retinoid X receptor(RXR) and forms a heterodimer.  When the THR binds to RXR, it alters genetic expression to a greater extent.

LPS in the liver lowers expression of these receptors(4).  Even with adequate levels of T3, it still can’t do its job.  Overall, this may raise levels of T3 in the blood leading to a state of hyperthyroidism based on serum T3 levels.  It could also raise reverse T3 levels which would block the effects of T3.

Layman’s breakdown: In order for any hormone to exert its effects, it must bind to a receptor and tell the DNA in the nucleus what to do.  Even if you have sufficient levels of the hormone, if receptor levels are low the hormone can’t exert its effect.

The liver and gut are 2 organs that process LPS extensively.  When LPS enters the liver, it lowers the number of thyroid hormone receptors which prevents thyroid hormone from exerting its effect.  This could lead to normal or high thyroid hormone levels despite a low energy state. 

Another receptor that helps the thyroid receptor function is the retinoid x receptor(RXR).  LPS also reduces levels of RXR which would lower the effect of thyroid hormone even more.

Tying it all together

LPS disrupts thyroid signaling throughout the body.  This disruption can lead to clinical symptoms of either hyper- or hypothyroidism without showing up on a clinical test.  If you feel you have symptoms of either and your doctor tells you your tests are fine, this is likely your problem.

Unfortunately this is a problem you want to address as soon as possible because it’s not going to go away on its own.  There are a number of ways you can lower LPS burden on the body provided you know it’s a problem.  We’ll be peeling away at these methods in future blogs, so stay tuned.

Do you have a thyroid problem that you can’t get a handle on?  Do your blood labs show normal thyroid function but your body is telling you different?  Have you seen improvement in your thyroid function after changing your lifestyle?  Did this blog convey the science to you in an understandable format?  Post comments and questions in the comment section below.