A healthy thyroid is a critical component of one’s overall health, and many people are struggling with thyroid disorders such as hypothyroidism, specifically Hashimoto’s autoimmune thyroiditis. In this autoimmune condition, the immune system attacks the thyroid gland, with the resulting inflammation leading to an underactive thyroid gland or hypothyroidism. Hashimoto’s disease is the most common form of hypothyroidism and was the first condition ever to be classified as an autoimmune disease.

I’ve written extensively about thyroid health, focusing on a multitude of environmental factors that may affect thyroid function, including gluten, gut health, stress, excess iodine, and vitamin D deficiency. I’ve also discussed why dietary changes are always the first step in treating Hashimoto’s, and why replacement thyroid hormone is often necessary for a successful outcome.

There is yet another nutritional factor that may play a role in thyroid health: selenium.

Selenium deficiency is not thought to be common in healthy adults, but is more likely to be found in those with digestive health issues causing poor absorption of nutrients, such as Crohn’s or celiac disease, or those with serious inflammation due to chronic infection. (1, 2) It is thought that selenium deficiency does not specifically cause illness by itself, but that it makes the body more susceptible to illnesses caused by other nutritional, biochemical or infectious stresses, due to its role in immune function. (3) Adequate selenium nutrition supports efficient thyroid hormone synthesis and metabolism and protects the thyroid gland from damage from excessive iodine exposure. (4)

Several research studies have demonstrated the benefits of selenium supplementation in treating autoimmune thyroid conditions. One study found that selenium supplementation had a significant impact on inflammatory activity in thyroid-specific autoimmune disease, and reducing inflammation may limit damage to thyroid tissue. (6) This may be due to the increase in glutathione peroxidase and thioredoxin reductase activity, as well as the decrease in toxic concentrations of hydrogen peroxide and lipid hydroperoxides which result from thyroid hormone synthesis. (7)

Another study followed patients for 9 months, and found that selenium supplementation reduced thyroid peroxidase antibody levels in the blood, even in selenium sufficient patients. (8) While these studies show promise for the use of selenium supplementation in preventing thyroid tissue damage, further research is needed to determine the long-term clinical effects of selenium treatment on inflammatory autoimmune thyroiditis.

Additionally, selenium is also essential for the conversion of T4 to T3, as deiodinase enzymes (those enzymes that remove iodine atoms from T4 during conversion) are selenium-dependent. As I’ve explained before, T3 is the active form of thyroid hormone, and low T3 can cause hypothyroid symptoms. A double-blind intervention study found that selenium supplementation in selenium deficient subjects modulated T4 levels, theoretically by improving peripheral conversion to T3. (9) In cases of severe selenium deficiency, conversion of T4 to T3 may be impaired, leading to hypothyroid symptoms. As T3 conversion is not performed by the thyroid, the dependence on selenoproteins for this conversion demonstrates how significant selenium deficiency could lead to hypothyroid symptoms.

So the question is, should you start supplementing with selenium if you have hypothyroidism, Hashimoto’s thyroiditis, or low T3 levels?

As the answer often is, it depends. These preliminary studies show the positive effects of selenium supplementation on inflammatory activity in autoimmune thyroid conditions, but the long term effects of supplementation on thyroid health are still unknown. And we know that selenium is an essential component of the enzymes that convert T4 to T3, but whether supplementation will increase serum T3 levels is unclear.

While it seems that selenium supplementation would be an obvious solution to poor thyroid function, long term consumption of high doses of selenium can lead to complications such as gastrointestinal upsets, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage. (10) Additionally, supplementing selenium in the context of low iodine status may actually aggravate hypothyroidism. Mario Renato Iwakura discusses this particular topic extensively on Paul Jaminet’s Perfect Health Diet blog.

For now, the best option for most people may be to include selenium-rich foods in the context of a healthy Paleo diet. Great sources of selenium include: brazil nuts, crimini mushrooms, cod, shrimp, tuna, halibut, salmon, scallops, chicken, eggs, shiitake mushrooms, lamb, and turkey. For those concerned with the high level of omega-6 fats in brazil nuts, it may be worth considering the fact that it only takes one or two brazil nuts per day to improve your selenium status and boost immune function. (11)

For those who choose to supplement, I consider 200 micrograms of selenium to be a safe supplemental dose for people with thyroid issues. The brand of selenium I recommend is Life Extension Super Selenium Complex, which has four different forms of selenium, totaling 200 micrograms. It also provides vitamin E, which works synergistically with selenium as an antioxidant. This dosage is enough to be therapeutic for treating selenium deficiency, but has a lower risk of causing overdose symptoms.

Making sure your selenium intake is optimal may give your immune system and thyroid the boost it needs to help it function better. Whether through selenium-rich foods or supplements, it is especially important for those managing thyroid conditions to ensure their selenium status is adequate.

Has anyone had any experience with selenium supplementation? Was it a positive or negative experience? Let me know in the comments below.

In this final article in the series on Low T3 Syndrome, we’ll discuss whether thyroid hormone replacement therapy is an appropriate treatment in these cases.

Unfortunately, there are few studies that have examined this question specifically, and even fewer that have explored the question of whether T4 or T3 (and which type of each) would be the best choice.

As a clinician, my primary concern is always primum non nocere, or “first, do no harm.” From this perspective it’s important to recognize that the changes seen in Low T3 Syndrome may represent a restorative physiological adaptation by the body to chronic illness. In other words, T3 levels are low because the body is attempting to conserve energy and resources to better cope with the challenges it is facing. Increasing thyroid hormone levels in this situation could conceivably have adverse effects.

For example, the changes observed in the thyroid axis in acute illness are similar to those observed in fasting, which can be interpreted as an attempt to reduce energy expenditure and protein wasting. (1) Giving fasting subjects thyroid hormone results in increased catabolism (breakdown). (2)

In cases of chronic illness, however, it is less clear what effect thyroid hormone replacement has. The few studies that have been done produced mixed results. (3)

Some studies show that treatment causes harm, others show no change, and still others show an improvement. After reviewing the literature on this, I’ve come to the following tentative conclusions:

• T4 is rarely, if ever, effective in Low T3 Syndrome and may even cause harm. This is probably due to the decreased conversion of T4 to T3 that is seen in chronic illness.
• T3 replacement has been shown to be consistently beneficial only in cardiac patients who’ve recently had surgery, heart failure or a transplant.

That said, I’ve heard anecdotal reports of improvement from people who have taken replacement T3 hormone for a condition called “Wilson’s Syndrome” (which does not exist in the scientific literature or according to any mainstream medical organizations). Wilson’s Syndrome refers to low basal body temperature and other nonspecific symptoms occurring in the presence of normal thyroid hormones.

I’ll be the first to admit that “lack of evidence is not evidence against”, and as I mentioned earlier, there’s not a lot of research on the effectiveness of T4 and T3 replacement therapy in Low T3 Syndrome. It may be that as we look into this further, we’ll discover a role for thyroid hormone replacement in these conditions.

That said, I think caution is warranted. Taking T3 when you don’t need it is potentially dangerous. It can significantly upregulate the metabolic rate and lead to cardiovascular complications in some patients. And, if the changes seen in Low T3 Syndrome are a compensatory adaptation of the body in response to chronic illness, increasing T3 levels artificially may have undesirable effects.

In the majority of cases of Low T3 Syndrome, I think it’s preferable to identify the underlying cause and treat that. As I discussed in articles #3 and #4 in this series, those causes most often include infections, autoimmunity and inflammation.

Have any of you tried thyroid replacement for Low T3 Syndrome? If so, what was your experience? Please let us know in the comments section.

Articles in this series:

• Low T3 Syndrome I: It’s Not About The Thyroid!
• Low T3 Syndrome II: Myths and Misconceptions
• Low T3 syndrome III: Inflammation Strikes Again
• Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
• Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?

In the last article in this series I discussed several lines of evidence suggesting that inflammation is one of the primary causes of Low T3 Syndrome.

In this article we’re going to discuss another common, but lesser known, cause: autoimmune hypopituitarism.

Say what? I know that’s a mouthful. Let’s break it down.

The pituitary gland is located just below the hypothalamus, but outside the blood-brain barrier. It’s primary job is to monitor the levels of hormones produced by various endocrine organs (like the thyroid), and release stimulating hormones (like TSH) that direct those organs to produce their respective hormones (like T4 and T3).

The pituitary gland can be the target of inflammatory response to local infections, cancer or autoimmune reactions. When an autoimmune mechanism is involved, lymphocytic adenohypophysitis (LAH) or autoimmune hypopituitarism are the terms used to describe the condition. (I’ll refer to this condition as LAH throughout the article.)

What is autoimmune hypopituitarism?

LAH is characterized by progressive destruction of pituitary tissue, which over time produces a decline in the function of the pituitary gland. (1) When the pituitary is damaged more than one hormone is affected, especially as the disease becomes more advanced.

It was originally believed that LAH occurred exclusively in pregnant women. (2) But although prevalence is still much higher in that population, we now know it also occurs in non-pregnant women, men and children. (3)

Adrenocorticotropin (ACTH) deficiency is most common (60%), followed by thyrotropin (TSH) deficiency (47%), gonadotropin (FSH/LSH) deficiency (42%), growth hormone deficiency (42%) and prolactin deficiency (34%).

What is remarkable about this condition is how unknown it is in spite of its prevalence. It’s true prevalence is unknown, but most investigators believe it is under-reported because it is often misdiagnosed. I’ve seen some estimates that it may affect up to 0.5% of the population and up to 40% of Hashimoto’s patients.

How is autoimmune hypopituitarism diagnosed?

The reason it’s so often misdiagnosed is that it’s difficult to pin down. It is strongly associated with other autoimmune diseases, which further complicates the clinical picture. In fact, concurrent autoimmune conditions are reported in 20-50% of LAH cases. (4)

Interestingly, Yoon et al. injected hamsters with Rubella virus glycoproteins and consistently induced LAH, as evidenced by autoantibodies to pituitary cells and infiltration of the pituitary gland by lymphocytes. (5) This finding suggests there may be some connection between viral infections and LAH.

Other investigators have identified antibodies to growth hormone (GH), thyrotropin (TSH), and luteinizing hormone (LH) in cases of LAH. (6) Unfortunately, the only conclusive test for LAH is a tissue biopsy, which is obviously problematic due to the location of the pituitary gland.

Low levels of the pituitary hormones can indicate LAH, but they can also be a sign of other functional problems with feedback in the hypothalamus or a primary problem with the hypothalamus itself.

What are the signs and symptoms of LAH?

The hallmark sign of LAH is atrophy of the gonads, adrenals and thyroid gland. Endocrine tissue is similar to muscle tissue in the sense that it will atrophy if it’s not stimulated regularly (similar to how men who take testosterone have shrunken testes).

Symptoms include:

• Headache
• Impaired vision
• Nausea
• Weakness
• Loss of appetite
• Hormone imbalances
• Hyperprolactinemia

However, LAH is difficult to characterize because it can mimic so many other conditions. A problem with the pituitary gland can affect the entire endocrine system, because the pituitary sends out the stimulating hormones that direct the organs (thyroid, adrenals, ovaries, testes, etc.) to produce their respective hormones. This is, of course, how LAH can lead to low T3 levels.

It’s also interesting to note that there appears to be a connection between LAH and celiac disease. (What isn’t connected with celiac disease?) Delvecchio et al found that about 40% of newly diagnosed celiac patients had anti-pituitary antobidies in their blood and it resulted in – at a minimum – growth hormone deficiency. (7) This is an important finding that I have rarely seen discussed.

How is autoimmune hypopituitarism treated?

Not very well, in the conventional model. Some doctors use immunosuppressants like prednisone, azothioprine and methotrexate, but the risks and side effects of these drugs can often be worse than the disease itself.

The first step to take is to make sure you’re eating a diet that is free of foods that tend to provoke an autoimmune response. A Paleo-type diet is the best starting place, but you may also want to remove dairy, nightshades and eggs for at least 30 days because those foods can be problematic for people with autoimmune disease.

It’s also important to focus on nutrients that support proper T-regulatory cell function, like vitamin D and glutathione, and nutrients that support overall immune health like vitamin C, iodine and selenium.

I would also consider low-dose naltrexone (LDN), a medication that is being used to successfully treat a wide range of autoimmune diseases – including Hashimoto’s and Graves’. In most cases I don’t recommend pharmaceuticals because they tend to suppress symptoms without improving function. LDN, however, actually improves the function of the body by upregulating endogenous endorphin production and balancing the immune system.

Articles in this series:

• Low T3 Syndrome I: It’s Not About The Thyroid!
• Low T3 Syndrome II: Myths and Misconceptions
• Low T3 syndrome III: Inflammation Strikes Again
• Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
• Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?

In the last article in this series we discussed some common myths and misconceptions about Low T3 Syndrome. In this article, we’re going to look at causes and mechanisms.

As I mentioned briefly before, researchers now believe that the fall in T3 seen in acute and chronic illness is most likely due to either impaired production of T3 in the thyroid (due to a change in the hypothalamic-pituitary-thyroid axis) or to a decrease in thyroid binding proteins. Both of these changes are caused by inflammation.

The thyroid set point

There’s been a lot of discussion recently in the blogosphere about the body fat set point, which is the complex neurobiological system that regulates weight. However, there is also a set point of the hypothalamic-pituitary-thyroid (HPT) axis that regulates the production of endocrine hormones, including TSH, T4 and T3.

It seems that the low TSH associated with illness, or the failure of TSH to rise in response to low T4 and T3, is caused by alterations in the set point of the HPT axis. There’s a set of neurons in the paraventricular nucleus (PVN) of the hypothalamus that is responsible for promoting TSH synthesis in the pituitary and regulating thyroid hormone synthesis.(1)

Post-mortem samples from patients who died after prolonged illness show a decrease of thyrotropin-releasing hormone (TRH) gene expression in the PVN.(2) Moreover, administering TRH and growth-hormone (GH) secretogogues to patients with prolonged illness at least partially restores TSH, T4 and T3 levels.(3) Both of these lines of evidence suggest that a change in the HPT axis is involved in the Low T3 Syndrome.

While there are multiple causes of such changes in the HPT axis, two of the more clinically relevant ones are inflammation and either a decline in serum leptin levels or leptin resistance.

Inflammatory cytokines released in the acute phase response (the inflammatory process) suppress the production of TRH in the PVN.(4) I’ll discuss the role of inflammation in more detail below.

Fasting or diminished calorie intake due to prolonged illness leads to decreased T3 levels, and this is thought to be mediated by a decrease in circulating leptin. Leptin prevents certain neurons (NPY/AgRP) from inhibiting TRH gene expression.(5)

Although I haven’t seen any studies on this specifically, it’s entirely conceivable that leptin resistance (which characterizes obesity) could have the same T3 decreasing effect. Most people are aware that poor thyroid function contributes to weight gain, but this mechanism suggests that it may also work in reverse: leptin resistance associated with overweight and obesity may contribute to poor thyroid function.

Thyroid binding proteins

When thyroid hormone is produced and released into the circulation by the thyroid gland, it’s bound (reversibly) to thyroxine-binding globulin (TBG), transthyretin and albumin. TBG is the major binding protein in humans, and under normal circumstances, less than 0.05% of thyroid hormone is unbound (“free”) in the blood.

It’s thought that only this tiny fraction of “free” thyroid hormone is able to enter the cell and perform the biological actions of thyroid hormone. This means that the concentration of total T4 and T3 (produced by the thyroid gland) is heavily dependent on the concentration of these binding proteins, while the free hormone concentrations are largely independent of them.

In Low T3 Syndrome, the concentration of thyroid binding proteins decreases as a consequence of the “acute phase response” (a.k.a. inflammation). For example, TBG levels decrease by as much as 60 percent in the 12 hours following bypass surgery.(6) In rodents, inflammation leads to a significant decrease in transthyretin, which is the major plasma thyroid hormone binding-protein in that species.(7) The fall in these binding proteins is probably what accounts for the decrease in total (protein-bound) T4 and T3 levels in acute and chronic illness.

Inflammation strikes again

Pro-inflammatory cytokines, which are chemical messengers involved in the inflammatory response, have been shown to contribute to Low T3 Syndrome in multiple ways.

Interleukin-6 (IL-6) is positively correlated with reverse T3 (an inactive form of T3) and negatively correlated with free T3.(8) In other words, the more IL-6 that is circulating in your blood, the less active thyroid hormone you’ll have available to your cells and tissues.

Administration of tumor necrosis factor alpha (TNF-alpha) to healthy individuals produces changes in thyroid hormones characteristic of Low T3 Syndrome.(9)

Administration of interferon alfa (IFN) to normal volunteers results in a decrease in T3 and TSH and a rise in reverse T3.(10)

Other studies have shown that lipopolysaccharide (LPS), a bacterial endotoxin, can downregulate TSH, T4 and T3 levels.(11) This explains the link between chronic bacterial infections and the Low T3 Syndrome, and it’s yet another connection between gut health and the thyroid (since many people with poor gut health have gut infections).

The takeaway of this article is that the primary mechanisms of Low T3 Syndrome are mediated by inflammation. That inflammation could be caused by an infection, autoimmune disease, obesity, diabetes or other chronic illness. Just about any disease you can think of is characterized by inflammation, so the list here is quite long.

In the next article I’ll discuss how – and if – Low T3 Syndrome should be treated.

Articles in this series:

• Low T3 Syndrome I: It’s Not About The Thyroid!
• Low T3 Syndrome II: Myths and Misconceptions
• Low T3 syndrome III: Inflammation Strikes Again
• Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
• Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?

In Low T3 Syndrome I, I introduced the Low T3 Syndrome (a.k.a. Euthyroid Sick Syndrome, Non-Thyroidal Illness Syndrome), provided some background on thyroid physiology and metabolism, and emphasized the fact that Low T3 Syndrome is not caused by a problem in the thyroid gland itself.

In this article we’re going to discuss common myths and misconceptions about Low T3 Syndrome and problems diagnosing it in a clinical setting.

This is important because there’s a lot of chatter around the internet these days about this condition. I’m getting a lot of questions about it and I see a lot of people diagnosing themselves with Euthyroid Sick Syndrome on the basis of what I feel is pretty sketchy evidence.

Early theories on Low T3 Syndrome

The typically accepted view in the scientific literature until quite recently was that the conversion of T4 to T3 is impaired in illness because of a decrease in the activity of D1 & D2 thyroid deoidinases (enzymes responsible for activation of thyroid hormone) in the liver, kidney, skeletal muscles and other peripheral tissues. (1)

The trigger for these changes was thought to be an increase in cortisol and pro-inflammatory cytokines, both of which typically occur in chronic illness.

Recently, however, this theory has been challenged. Researchers now argue that the changes seen in D1, D2 & D3 (deodinase) expression may be the consequence – not the cause – of changes in T4 and T3 levels. (2)

This is supported by studies on D1, D2 and D3 knockout mice subjected to treatment with lipopolysaccharide (LPS), an pro-inflammatory endotoxin. These mice, which don’t have any thyroid deiodinase activity, experienced the same decrease in T4 and T3 as wild-type mice. (3)

Also, when wild-type mice are injected with LPS, the fall in T4 and T3 precedes the decline in deiodinase activity (4), and in humans it has been shown that decreased D2 activity doesn’t contribute to Low T3 Syndrome in either prolonged or acute illness. In fact, D2 expression increases two- to three-fold in chronic illness states. (5)

However, evidence now suggests that the fall in T3 found in acute illness is more likely to be caused by impaired production of T3 in the thyroid gland (in turn caused by decreased hypothalamic production of TRH and pituitary production of TSH), and the reduction in thyroid horomone-binding proteins in the serum. (6) We’ll discuss these mechanisms in more detail in the next article.

Problems with testing and diagnosis

One of the biggest problems with getting a better understanding of Low T3 Syndrome is that the methodologies for testing thyroid hormones in the general population are often inappropriate or outdated.

First, it’s often the case that only total T4 and T3 are tested, rather than free T4 and free T3. While total T4 and T3 give us important information about what the thyroid gland itself is producing, free T4 and T3 tell us how much thyroid hormone is actually available at the cellular level to exert its metabolic effects.

But even when free T4 and T3 are tested, the results are often inaccurate because of the methods used. Although it is often claimed that free T4 is low in patients with Low T3 Syndrome, when the proper methodology is used, free T4 is rarely low – and is often normal or even high. (7)

In fact, is studies using reliable assays for free T4, around 50% of patients had low total T4 but only 2% had low free T4! (8)

The situation is even more problematic, in some ways, with the measurement of free T3 – especially because the free T3 level is fundamental to the diagnosis of Low T3 Syndrome.

It is unequivocal in the literature that total T3 falls during illness, and that the degree of the fall is directly proportional to the severity of the illness. And most routine methods used to measure free T3 commercially and even in research settings tend to show that it drops right along with total T3.

However, results from two studies that have used an improved method for free T3 analysis have found that illness results only in a modest fall in free T3. In fact, free T3 levels were only 10% lower in sick patients than in healthy controls. (9)

Another study using this method found that while 70-80% of sick patients had low total T3, only 27% of them had low free T3. (10)

Why does this matter? Two reasons:

• First, a lot of people diagnosed with Low T3 Syndrome may not actually have low free thyroid hormones. This is a concern because some people are supplementing with T4 and/or T3 under the false impression that their hormones are low.
• Second, it implies that the significant changes seen in total T4 and T3 in Low T3 Syndrome are largely due to changes in the serum binding capacity for thyroid hormones.

We’ll discuss each of these points in more detail in the posts to follow.

Articles in this series:

• Low T3 Syndrome I: It’s Not About The Thyroid!
• Low T3 Syndrome II: Myths and Misconceptions
• Low T3 syndrome III: Inflammation Strikes Again
• Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
• Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?

Hypothyroidism involves high levels of thyroid stimulating hormone (TSH) and low levels of the thyroid hormones T4 and T3.

However, in my clinical practice I frequently see people with low levels of T3 with normal T4 and either low or normal TSH. This condition has been reported on in the medical literature for years but it is rarely acknowledged or discussed in conventional medical settings. Most doctors (even endocrinologists) do not seem to know what causes it, or what to do about it. (I know this because I always ask my patients with this syndrome what their doctors said about it, and my patients’ response is almost always some variation of “not much”).

This particular pattern goes by three different names in the medical literature: Euthyroid Sick Syndrome (ESS), Non-thyroidal Illness Syndrome (NTIS), and Low T3 Syndrome.

NTIS has become the term of choice in the literature. However, I’m going to use Low T3 Syndrome in these articles because it’s more descriptive and accessible to the layperson.

What’s most important to understand about this condition is that, although it does involve low levels of T3 (the most active form of thyroid hormone), it is not caused by a problem with the thyroid gland. This is a crucial distinction and it’s what distinguishes Low T3 Syndrome from “garden-variety” hypothyroidism.

In this series we’re going to discuss 1) what causes Low T3 Syndrome, 2) it’s clinical significance, and 3) if it should be treated, and if so, how.

But first we need to lay the foundation with a little basic thyroid physiology.

Basic thyroid physiology

In order to understand Low T3 Syndrome, you’ll need a basic understanding of thyroid physiology. Regulation of thyroid metabolism can be broken down into the following five steps:

1. The hypothalamus (a pea-sized gland in the brain) monitors the levels of thyroid hormone in the body and produces thyrotropin releasing hormone (TRH).
2. TRH acts on the anterior pituitary (directly below the hypothalamus, but outside of the blood-brain barrier) to produce thyrotropin, a.k.a. thyroid stimulating hormone (TSH).
3. TSH acts on the thyroid gland, which produces thyroxine (T4) and triiodothyronine (T3), the primary circulating thyroid hormones. The thyroid produces T4 in significantly greater quantities (in a ratio of 17:1) than T3, which is approximately 5x more biologically active than T4.
4. T4 is converted into the more active T3 by the deiodinase system (D1, D2, D3) in multiple tissues and organs, but especially in the liver, gut, skeletal muscle, brain and the thyroid gland itself. D3 converts T3 into an inactive form of thyroid hormone in the liver.
5. Transport proteins produced by the liver – thyroid binding globulin (TBG), transthretin and albumin – carry T4 and T3 to the tissues, where they are cleaved from their protein-carriers to become free T4 and free T3 and bind to thyroid hormone receptors (THRs) and exert their metabolic effect.

Mechanisms of Low T3 Syndrome

As you can see, the production, distribution and activation of thyroid hormone is complex and involves several other organs and tissues other than the thyroid gland itself.

Hypothyroidism is a defect in step #3, because it typically involves a dysfunction of the thyroid gland itself – most often caused by autoimmune disease (Hashimoto’s, Ord’s, Graves’) and/or iodine deficiency.

However, in Low T3 Syndrome, the problem generally occurs in steps #1, #2, #4 and #5. None of those steps are directly related to the function of the thyroid gland itself.

More specifically, Low T3 Syndrome can include the following mechanisms:

• Modifications to the hypothalamic-pituitary axis
• Altered binding of thyroid hormone to carrier proteins
• Modified entry of thyroid hormone into tissue
• Changes in thyroid hormone metabolism due to modified expression of the deiodinases
• Changes in thyroid hormone receptor (THR) expression or function

Low T3 Syndrome in acute and chronic illness

Most of the studies on Low T3 Syndrome have been done on people suffering from acute, life-threatening illness. In the intensive care unit, the prevalence of abnormal thyroid function tests is remarkably high. More than 70% of patients show low T3 and around 50% have low T4.

Many of these studies have indicated a direct relationship between Low T3 Syndrome the severity and both short- and long-term outcome of disease. The lower the T3 level in critically ill patients, the worse the outcome tends to be.

However, studies examining thyroid hormone replacement in these situations have shown mixed results. In most cases – with the exception of cardiovascular disease – taking thyroid hormone did not improve outcomes. We’ll discuss this in more detail later.

Recently, more attention has been given to Low T3 Syndrome in non-critical, chronic illness. Specifically, the question on everyone’s mind (including mine) is whether thyroid hormone replacement is useful in this situation, or if – as some have suggested – it could even be harmful.

In emotional, psychological or physiological stress, the body will convert excess T4 to reverse T3 (rT3) as a means of conserving energy for healing and repair. It is at least possible, therefore, that replacing thyroid hormone in these cases may not be beneficial.

On the other hand, in those suffering from long-term chronic illness, Low T3 Syndrome may be more reflective of pathology than adaptation, and this group may benefit from T4 or T3 supplementation.

We’ll explore all of these questions in more detail in the articles to follow, and I’ll also share some of my observations from my clinical practice. Stay tuned!

Articles in this series:

• Low T3 Syndrome I: It’s Not About The Thyroid!
• Low T3 Syndrome II: Myths and Misconceptions
• Low T3 syndrome III: Inflammation Strikes Again
• Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
• Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?

In the first post in this series, we established that hypothyroidism is caused by an autoimmune disease (called Hashimoto’s) in the vast majority of cases. Since then, we’ve explored the role of gluten intolerance, vitamin D deficiency, supplemental iodine, blood sugar imbalances, adrenal stress and a leaky gut in perpetuating the autoimmune attack and disrupting thyroid function. We’ve discussed why dietary changes are always the first step in treating Hashimoto’s, and why replacement thyroid hormone is often necessary for a successful outcome.

What we haven’t discussed yet, however, are specific strategies for bringing the immune system back into balance. That will be the focus of this article.

Originally, I planned to go into considerable detail on the specific mechanisms of immune dysfunction that occur with Hashimoto’s, including a review of immunology, immune system classification (i.e. Th1 or “cell-mediated” immunity vs. Th2 or “humoral immunity”) and immune cell organization. It quickly became clear that such an approach would require an entire series of its own.

So, as fascinating as all of that stuff is, I decided to cut to the chase and focus on the practical, clinical applications. But there’s a caveat. Although I’ll be offering some general guidelines here for how to balance the immune system, if you have Hashimoto’s (or any other autoimmune condition) it’s in your best interest to find someone who understands immunology and is current with the latest nutritional and botanical protocols for treating autoimmune disease.

Why? Because autoimmune disease is not only extremely complex, but also highly individualized. Hashimoto’s in one person is not the same as Hashimoto’s in the next person. In one person, Hashimoto’s could present as a Th1-dominant condition. In another, it may present as Th2 dominant. In still another, both the Th1 and Th2 systems might be overactive, or underactive. And each of these cases requires a different approach. For example, botanicals like echinacea and astragalus stimulate the Th1 system. If someone with Th1 dominant Hashimoto’s takes these herbs, they’ll quite possibly get worse. On the other hand, antioxidants like green tea and Gotu Kola stimulate the Th2 system, and would be inappropriate for those with Th2 dominant Hashimoto’s. (For more information on the specifics of Hashimoto’s autoimmune physiology, see this article on Dr. Kharrazian’s blog and pick up a copy of his book.)

The good news, though, is that there are general approaches to balancing the immune system that are suitable for all types of Hashimoto’s regardless of the specific pattern of immune dysregulation. These approaches can be broken into three categories: removing autoimmune triggers, enhancing regulatory T cell function and reducing inflammation.

Removing autoimmune triggers

We’ve already discussed the role of gluten, iodine, stress and a leaky gut in triggering an autoimmune response. Other potential triggers include estrogens, infectious agents, and environmental toxins.

Estrogen fluctuations can trigger the gene expression of Hashimoto’s in the presence of inflammation and genetic susceptibility. In addition to turning on the genes associated with Hashimoto’s, estrogen surges have been shown to exacerbate the autoimmune attack on the thyroid. This may explain why the expression of Hashimoto’s is so common during pregnancy and perimenopause – both times when estrogen may be fluctuating wildly.

Environmental toxins are associated with autoimmune disease, and Hashimoto’s is no exception. Certain antigens like mercury that bypass our barrier system cause a potent immune response that can become chronic and overactive. If you suspect environmental toxicity may be contributing to your condition, it’s probably a good idea to get a test for chemical haptens and heavy metal antibodies.

Autoimmune thyroid disease has also been associated with a variety of infectious agents, including Rubella, Rubeolla, Epstein-Barr Virus, Retrovirus, Influenza B virus, Coxsakie virus and Yersinia. The mechanism in all cases is theorized to be cross-reaction between thyroid stimulating hormone (TSH) receptors and infectious agents. Once again, if you suspect an infectious agent is involved in your condition, a screening for these pathogens is a good idea.

Enhancing regulatory T cell function

These strategies are all designed to enhance the function of regulatory T cells (also referred to as the Th3 system). Regulatory T cells are used to balance the activity between T-helper cells (Th1 & Th2) and T-suppressor cells (which “turn off” the immune attack).

Vitamin D has been shown to influence regulatory T cells, which in turn modulate T helper cell expression and balance the Th1 and Th2 response. For more on this see The Role of Vitamin D Deficiency in Thyroid Disorders.

The gut flora play a significant role in both cell-mediated (Th1) and humoral (Th2) immunity. Studies show that this protective role can be maintained and modulated by taking probiotics. Specific probiotic strains can influence the secretion of cytokines to help direct naïve helper T cells towards either a Th1 dominant, cell-mediated immune response or towards a Th2 dominant, humoral immune response.

Acupuncture has recently been shown to regulate the Th1 and Th2 immune response. In this study of patients with depression, both Prozac and acupuncture were shown to reduce inflammation. But only acupuncture restored the balance between the Th1 and Th2 systems. In another study, acupuncture reduced inflammation and lessened the symptoms of asthma by regulating the balance between Th1 and Th2 cytokines.

Reducing inflammation

Essential fatty acids (EFAs) play an important role in preventing and reducing inflammation. I’ve written an entire series of articles on this topic, which I’d recommend reading if you haven’t already.

The ideal ratio between omega-6 and omega-3 fatty acids is between 1:1 and 3:1. The average American ratio is closer to 25:1, and as high as 30:1, thanks to diets high in processed and refined foods. The result of this imbalance is – among other things – inflammation.

Two steps are required to bring this ratio back into balance. First, dramatically reducing consumption of omega-6 fats, and second, moderately increasing consumption of omega-3 fats. I explain how to do this in considerable detail in this article.

Another benefit of increasing intake of omega-3 fatty acids is that they have also been shown to help balance the Th1 and Th2 systems.

Aside from ensuring a proper balance of omega-3 and omega-6 fatty acids, following an anti-inflammatory diet/lifestyle and avoiding dietary triggers like gluten and iodine is essential.

Putting these general approaches to balancing the immune system into action should give you a good start towards getting the autoimmunity under control. But if you don’t see the results you’d like, I’d recommend working with someone who knows how to address your particular immune imbalance more specifically.

I often get comments and emails from people asking me which thyroid hormone I think is best. My answer is always the same: “It depends.” As much as some practitioners would like to make us believe, there is simply no “one size fits all” approach to thyroid hormone replacement.

Statements like “Synthroid is best” or “I prefer to use synthetic T4 with my patients” or “I only use bio-identical hormones” demonstrate a lack of understanding of thyroid pathology. Why? Because, as I’ve explained in this series, the underlying causes of thyroid dysfunction are diverse.

Giving all patients the same thyroid medication without understanding the mechanisms involved is analogous to not checking a patient’s blood type before doing a transfusion. Granted, the consequences may not be as severe, but the underlying principle is the same.

Before we continue, let me remind you that I’m not a doctor and I’m not offering you medical advice. My intent is to educate you about the various considerations that should be made when choosing a thyroid medication, so you can discuss them with your doctor. Understood? Great. Let’s move on.

Choosing the right thyroid medication requires answering the following three questions:

1. What’s the mechanism that led to the need for medication in the first place?
2. Are there any mechanisms that may interfere with the actions of the medication?
3. Does the patient have sensitivities to the fillers used in the medications?

Let’s look at each of these in turn.

What’s the mechanism that led to the need for medication in the first place?

If you’ve been following this series, you know that there’s no single cause for low thyroid function. Do you have an autoimmune disease (Hashimoto’s) causing destruction of your thyroid gland? Do you have high levels of estrogen causing an increase in thyroid binding proteins and a decrease in free thyroid hormone? Do you have a systemic inflammatory condition affecting your ability to convert T4 to T3, or decreasing the sensitivity of the cells in your body to thyroid hormone?

In order to choose the right hormone, you have to know what the underlying mechanism causing the dysfunction is. Let’s look at an example.

Say you have a problem converting T4 to T3. In this situation, your TSH may or may not be slightly elevated, but let’s say it is, and your doctor prescribes Synthroid. Synthroid is a synthetic T4 hormone. Will this help you?

No. It won’t help because your problem in this example isn’t a lack of T4, it’s an inability to convert T4 to the active T3 form. You could take T4 all day long, and it won’t do a thing unless your body can convert it.

The first step in this case would be to address the causes of the conversion problem (i.e. inflammation), in the hopes that you may not need replacement hormone. If that doesn’t work, though, what you’d need in this situation is either a so-called bio-identical hormone that has a combination of T4 and T3, or a synthetic T3 hormone (like Cytomel). These will deliver the T3 you need directly, bypassing the conversion problem.

Are there any mechanisms that may interfere with the actions of the medication?

The vast majority of long-term hypothyroid patients that haven’t been properly managed find that they constantly need to increase the dose of their medication, or switch to new medications, to get the same effect.

There are several reasons for this. First, inflammation (which is characteristic of all autoimmune diseases, and Hashimoto’s is no exception) causes a decrease in thyroid receptor site sensitivity. This means that even though you may be taking a substantial dose of replacement hormone, your cells aren’t able to utilize it properly.

Second, elevations in either testosterone or estrogen (extremely common in hypothyroid patients) affect the levels of circulating free thyroid hormone. For example, high levels of estrogen will increase levels of thyroid binding protein. Thyroid hormone is inactive as long as it’s bound to this protein. If you take thyroid replacement, but you have too much binding protein, there won’t be enough of the active form to produce the desired effect.

Third, there are several medications that alter the absorption or activity of T4. These include commonly prescribed drugs like antibiotics & antifungals (i.e. sulfonamides, rifampin, keoconazole), anti-diabetics (Orinase, Diabinese), diuretics (Lasix), stimulants (amphetamines), cholesterol lowering medications (Colestid, Atromid, LoCholest, Questran, etc.), anti-arrhythmia medications (Cordarone, Inderal, Propanolol, Regitine, etc.), hormone replacement (Premarin, anabolic steroids, growth hormone, etc.), pain medication (morphine, Kadian, MS Contin, etc.), antacids (aluminum hydroxides like Mylanta, etc.) and psychoactive medications (Lithium, Thorazine, etc.).

All of these factors must be considered if a particular medication isn’t having the desired effect.

Does the patient have sensitivities to the fillers used in the medications?

Another important consideration in choosing the right hormone is the fillers contained in each medication. Many popular thyroid medications contain common allergens such as cornstarch, lactose and even gluten. As I explained in a previous post, most hypothyroid patients have sensitivities to gluten, and many of them also react to corn and dairy (which contains lactose).

Synthroid, which is one of the most popular medications prescribed for hypothyroidism, has both cornstarch and lactose as a filler. Cytomel, which is a popular synthetic T3 hormone, has modified food starch – which contains gluten – as a filler.

Even the natural porcine products like Armour suffer from issues with fillers. In 2008, the manufacturers of Armour reformulated the product, reducing the amount of dextrose & increasing the amount of methylcellulose in the filler. This may explain the explosion of reports by patients on internet forums and in doctor’s offices that the new form of Armour was either “miraculous” or “horrible”. Those that had sensitivities to dextrose were reacting less to the new form, and experiencing better results, while those that had sensitivities to methylcellulose were reacting more, and experiencing worse results.

The best choice in these situations is to ask your doctor to have a compounding pharmacy fill the prescription using fillers you aren’t sensitive to. Unfortunately, insurance companies sometimes refuse to cover this.

Other considerations

Another common question that is hotly debated is whether bio-identical or synthetic hormones are best. Once again, the answer is: “It depends.” In general I think bio-identical hormones are the best choice. A frequently perpetuated myth (in Synthroid marketing, for example) is that the dosages and ratio of T4:T3 in Armour aren’t consistent. Studies have shown this to be false. Armour contains a consistent dose of 38 mcg T4 and 9 mcg T3 in a ratio of 4.22:1.

However, in some cases patients do feel better with synthetic hormones. One reason for this is that a small subset of people with Hashimoto’s produce antibodies not only to their thyroid tissue (TPO and TG), but also to their own thyroid hormones (T4 and T3). These patients do worse with bio-identical sources because they increased the source of the autoimmune attack.

Another issue is the use of T3 hormones. As we’ve discussed, T3 is the active form and has the greatest metabolic effects. The flip side of this, however, is that it’s far easier to “overdose” on T3 than on T4. Patients with trouble converting T4 to T3 do well on synthetic T3 or bio-identical combination T4:T3 products. But for many patients with Hashimoto’s, which is can present with alternating hypo- and hyperthyroid symptoms, T3 can push them over the edge. They are generally better off with T4 based drugs.

As you can see, the best thyroid hormone for each patient can only be determined by a full thyroid work-up and exam, followed by trial and error of different types of replacement medications. Such a work-up would include not just an isolated TSH test, but also a more complete thyroid panel (including antibodies), other important blood markers (glucose, lipids, CBC with diff, urinary DPD, etc.) and possibly a hormone panel. A history must be taken with particular attention paid to the patient’s subjective response to replacement hormones they may have tried in the past.

Unfortunately, this rarely happens in the conventional model, where the standard of care is to test only for TSH. If it’s elevated, the patient will get whatever hormone that particular practitioner is fond of using without any further investigation. And all too often, as many of you can attest, this simplified and incomplete approach is doomed to failure.

If you’ve been reading this blog for a while, you might be surprised by the title of this post. I’ve been critical of pharmaceutical approaches in the past, and in general, I recommend avoiding the use of medication whenever possible.

However, I have no problem with pharmaceuticals if:

1. they work,
2. they do more good than harm, and;
3. there are no non-drug alternatives with the same effect.

It turns out that thyroid medication meets these criteria in cases of hypothyroidism with chronically elevated TSH. Elevated TSH indicates that the body is not producing enough thyroid hormone to meet metabolic needs. And thyroid hormone is so important to the proper function of the body that the benefits of replacing it far outweigh any potential side effects of the medication.

Remember that every cell in the body has receptor sites for thyroid hormone. Thyroid hormones are responsible for the most basic and fundamental aspect of physiology: the basal metabolic rate. Since the basal metabolic rate affects every system of the body, low thyroid hormone causes a global decline in cellular function.

Here’s a list of things that can go wrong when thyroid hormones are low. It’s not complete, but it should give you some idea of how important the thyroid is to proper function.

• Decreased energy production and metabolism in all cells of the body
• Decreased bone quality and increase in fractures
• Elevated cholesterol
• Impaired phase II detoxification
• Anemia
• Decreased stomach acid production
• Constipation, intestinal dysbiosis, malabsorption
• Intestinal inflammation
• Blood sugar imbalances
• Gallstone formation
• Vascular and arterial plaquing
• Neurodegeneration, cognitive problems, depression
• Weight gain
• Hair loss
• Dry skin
• Cold hands and feet
• Infertility and reproductive dysfunction
• Weakened immune system

I could go on, but I think you get the point. If your thyroid hormones are low, you can’t be healthy. Period.

90% of people with hypothyroidism in the U.S. have Hashimoto’s disease. Hashimoto’s is an autoimmune condition that causes destruction of the thyroid gland over time. As this destruction progresses, the thyroid gland becomes less and less able to produce enough hormones to meet metabolic needs. This is reflected in an increase in thyroid-stimulating hormone (TSH).

Persistently elevated TSH is a sign that the body needs more thyroid hormone than it can produce on its own. This is one clear sign that it’s time for replacement medication. But it isn’t the only one. Some people with TSH in the normal lab range still find that they benefit from replacement.

Note that I’m not saying everyone with hypothyroid symptoms should be on medication. In a previous post, I discussed 5 different patterns of low thyroid function that present with normal TSH levels. These include underconversion of T4 to T3, problems with thyroid binding proteins, pituitary dysfunction and thyroid receptor-site resistance. In these cases, the problem isn’t with the thyroid gland itself or its ability to produce enough hormones, but is either “upstream” (in the case of pituitary dysfunction) or “downstream” (in the case of conversion problems, binding protein issues or resistance.) For these patterns, replacement hormones are often unnecessary.

There are many in my profession (natural healthcare) that vehemently oppose the use of medication under any circumstances. I think that’s foolish. I’m more concerned about the dangers of Big Pharma than most. But that doesn’t mean we should ignore the important role drugs play in treating certain conditions.

In fact, my philosophy on healthcare can be simply stated as: whatever works best and causes the least harm. It’ not often that a drug fits the bill. But in the case of hypothyroidism with elevated TSH, I believe replacement medication is a necessary part of a larger strategy that includes balancing blood sugar, adrenals and the immune system and fixing the gut.

In the next post I’ll discuss the many different considerations when choosing a thyroid medication.

Dr. Kharrazian has written an excellent post over at his blog about the importance of proper diet in the treatment of Hashimoto’s. He covers all the bases: the importance of going gluten-free, why gluten-free isn’t enough for most people, how to identify and address food sensitivities, how to balance blood sugar, and how to deal with the psychological and emotional resistance that may arise when making significant dietary changes.

The main obstacle most Americans face in implementing dietary changes, as Dr. K points out, is their addiction to the idea of a “quick fix”:

Americans are infatuated with pills, thanks to decades of conditioning from the pharmaceutical industry. It doesn’t matter whether they come from the pharmacy or the health food store, we have a cultural fixation with finding that magic bullet. It’s no wonder—making genuine, lasting changes to your health takes hard work and discipline, the two last things you’ll see advertised on commercials during your favorite television show.

As long as this mentality prevails, we’ll continue to suffer from increasing rates of disease and morbidity, and our “disease-care” system will continue to buckle and, eventually, collapse.

Dietary and lifestyle changes aren’t easy, but they’re the key to promoting health and preventing disease. And that’s just as true with Hashimoto’s as it is with type 2 diabetes and heart disease.

Note: This will be my last post until the end of August. My wife and I are going up to the Sierras to hike and soak in the hot springs for a few days before the big acupuncture licensing exam next Tuesday. The day after that we head to southern Mexico to surf and relax on the beach for a couple of weeks.

I won’t have time to respond to comments while I’m away, but please do leave them and I’ll answer when I come back. I’ve got a few more articles in the thyroid series, and next up after that will be type 2 diabetes & metabolic syndrome. Have a great August!

Vitamin D is all the rage. It seems like every day another article is published in medical journals or the mainstream press about the dangers of vitamin D deficiency, and the benefits of supplementation. In this article we’re going to discuss the impacts of vitamin D on thyroid physiology and wade into the increasingly murky topic of vitamin D supplementation – specifically as it relates to thyroid disorders.

Vitamin D deficiency has been associated with numerous autoimmune diseases in the scientific literature. Vitamin D plays an important role in balancing the Th1 (cell-mediated) and Th2 (humoral) arms of the immune system. It does this by influencing T-regulatory (Th3) cells, which govern the expression and differentiation of Th1 and Th2 cells.

Vitamin D deficiency is also specifically associated with autoimmune thyroid disease (AITD), and has been shown to benefit autoimmune-mediated thyroid dysfunction.

Vitamin D has another little-known role. It regulates insulin secretion and sensitivity and balances blood sugar. This recent paper showed that vitamin D deficiency is associated with insulin resistance. And as we saw in a previous article, insulin resistance and dysglyemcia adversely affect thyroid physiology in several ways.

“Okay, big deal,” you say. “I’ll just take vitamin D supplements or get more sun.”

Not so fast. Research over the past two decades has identified a variety of mechanisms that reduce the absorption, production and biologic activity of vitamin D in the body.

• Since vitamin D is absorbed in the small intestine, a leaky and inflamed GI tract – which is extremely common in people with low thyroid function – reduces the absorption of vitamin D.
• High cortisol levels (caused by stress or medications like steroids) are associated with lower vitamin D levels. They synthesis of active vitamin D from sunlight depends on cholesterol. Stress hormones are also made from cholesterol. When the body is in an active stress response, most of the cholesterol is used to make cortisol and not enough is left over for vitamin D production.
• Obesity reduces the biologic activity of vitamin D. Obese people have lower serum levels of vitamin D because it gets taken up by fat cells.
• Not eating enough fat or not digesting fat properly reduces absorption of vitamin D. Vitamin D is a fat-soluble vitamin, which means it requires fat to be absorbed. People on low-fat diets, and people with conditions that impair fat absorption (like IBS, IBD, gall bladder or liver disease) are more likely to have low levels of vitamin D.
• A variety of drugs reduce absorption or biologic activity of vitamin D. Unfortunately, these include drugs that are among the most popular and frequently prescribed – including antacids, replacement hormones, corticosteroids, anticoagulants and blood thinners.
• Aging reduces the conversion of sunlight to vitamin D becomes.
• Inflammation of any type reduces the utilization of vitamin D.

“Okay, fine,” you say. “I’ll just get my vitamin D measured, and if it’s low, I’ll take supplements.”

If only it were that simple. We now know that certain people with normal serum levels of vitamin D still suffer from deficiency symptoms. How is this possible?

In order for circulating vitamin D to perform its functions, it must first activate the vitamin D receptor (VDR). The problem is that many people with autoimmune disease have a genetic polymorphism that affects the expression and activation of the VDR and thus reduces the biologic activity of vitamin D. Studies have shown that a significant number of patients with autoimmune Hashimoto’s disease have VDR polymorphisms.

In plain English, here’s what this means: if you have low thyroid function, you might be experiencing vitamin D deficiency even if your blood levels of vitamin D are normal. It also means that, if you have a VDR polymorphism, it’s likely you’ll need to have higher than normal blood levels of vitamin D to avoid the effects of vitamin D deficiency.

“Okay, I get it,” you say. “I may need higher vitamin D levels than the average person if I have one of those genetic defects. So tell me what my levels should be!”

Well, this is where we venture into murky territory. The question of how high vitamin D levels should be is very difficult to answer in the case of someone with autoimmune thyroid disease. Studies suggest the optimal 25(OH)D level is 35 ng/mL for the average person. Some researchers (notably Dr. John Cannell and colleagues at the Vitamin D Council) have suggested that 50 ng/mL should be the minimum level.

The bulk of the evidence, however, doesn’t support that claim. For starters, the other authors of the study Dr. Cannell used as the basis for his 50 ng/mL recommendation came to a very different conclusion from the same data. In the paper they published in the American Journal of Clinical Nutrition, they wrote that their data confirmed the previously acknowledged optimal level of 35 ng/mL – not the 50 ng/mL suggested by Dr. Cannell.

What’s more, some recent studies have shown that higher isn’t better when it comes to vitamin D. A study in the American Journal of Medicine found that, in most people, maximum bone density occurs at 25(OH)D levels between 32-40 ng/mL. When levels are pushed above 45 ng/mL, as recommended by Dr. Cannell, bone density starts to decrease. Another study published in the European Journal of Epidemiology found that South Indians 25(OH)D levels above 89 ng/mL were three times more likely to have suffered from heart disease than those with lower levels.

If you’ve been following this blog for a while, you know that we don’t put too much faith in epidemiological studies. They don’t prove causation. They only show a relationship between two variables. But the relationship of vitamin D to calcium levels also provides a plausible mechanism by which high 25(OH)D levels could increase the risk of heart disease.

Complicating the matter further, recent work by researcher Chris Masterjohn suggests that the harmful effects of vitamin D toxicity are at least in part caused by a corresponding deficiency in vitamins A & K2. The fat-soluble vitamins A, D & K2 work synergistically, as Masterjohn has described in his Cod Liver Oil Debate article and a recently published scientific paper.

Masterjohn’s hypothesis, which has been confirmed by others, raises the possibility that the higher levels of 25(OH)D that were linked with lower bone density and heart disease may be safe if vitamin A & K2 levels are sufficient. Unfortunately, there is no clinical evidence (that I’m aware of) that helps us to answer this question.

“Okay, okay,” you say. “Just tell me how much to take already!”

I wish it were easier to answer this question. Really, I do. I think about it a lot for my own patients. The research is clear that 35 ng/mL is the minimum level for optimum function for healthy people. But people with autoimmune thyroid conditions aren’t healthy. They often have GI disorders, inflammation, stress, excess weight, VDR polymorphisms and other factors that impair their production, absorption and utilization of vitamin D. This suggests that the minimum 25(OH)D level for those with AITD may be significantly higher than for healthy people.

My current approach with these patients is to do a cautious trial of raising their serum levels to a range of 60-70 ng/mL. If their symptoms improve at this level, I will then switch them to a maintenance dose while watching for clinical signs of vitamin D toxicity. These include kidney stones (also a sign of vitamin K2 deficiency), low appetite, nausea, vomiting, thirst, excessive urination, weakness and nervousness. I will also monitor serum calcium levels, because elevated calcium in the blood is a sign of vitamin D toxicity and a significant risk factor for cardiovascular disease (especially in the presence of vitamin K2 deficiency). Calcium levels above 11-12 mg/dL (or 2.8-3 mmol/L) are indicative of vitamin D toxicity.

I will also make sure these patients are getting adequate amounts of vitamin K2 and vitamin A in their diets. Sources of vitamin A include organ meats, cod liver oil and full-fat milk and cream from grass-fed cows. Sources of vitamin K2 include fermented foods like natto, hard cheeses and kefir as well as egg yolks and butter from grass-fed cows. I may also use a vitamin K2 supplement (MK-4/MK-7 combo) if patients can’t tolerate fermented foods.

Finally, if you’re interested in finding out if you have a VDR polymorphism that could be affecting your metabolism of vitamin D, Genova Diagnostics has an Osteogenomics panel that tests for them. I’m not sure how much value this test has clinically, however, since it doesn’t provide any information about how the VDR polymorphism affects vitamin D metabolism in each specific case. That’s still something that would have to be figured out using the “trial and error” process I described above.

In time we can hope that the explosion of research being conducted on vitamin D will lead to more clarity on the question of appropriate serum 25(OH)D levels for people with autoimmune diseases. For now, we have to make our best guess based on clinical results and anecdotal reports.

We’ve already talked about how blood sugar imbalances and poor gut health can lead to hypothyroidism and Hashimoto’s. The harmful effects of adrenal stress complete the triad.

The adrenals are two walnut-shaped glands that sit atop the kidneys. They secrete hormones – such as cortisol, epinephrine and norepinephrine – that regulate the stress response. But these hormones play other crucial roles, many of which are directly related to thyroid health. In fact, as we’ll see in this article, proper thyroid function depends on healthy adrenal glands.

Most people are aware of the obvious forms of stress that affect the adrenal glands: impossibly full schedules, driving in traffic, financial problems, arguments with a spouse, losing a job and the many other emotional and psychological challenges of modern life.

But other factors not commonly considered when people think of “stress” place just as much of a burden on the adrenal glands. These include blood sugar swings, gut dysfunction, food intolerances (especially gluten), chronic infections, environmental toxins, autoimmune problems and inflammation. All of these conditions sound the alarm bells and cause the adrenals to pump out more stress hormones. In this context, stress is broadly defined as anything that disturbs the body’s natural balance (homeostasis).

Adrenal stress is probably the most common problem we encounter in functional medicine, because nearly everyone is dealing with at least one of the factors listed above. Symptoms of adrenal stress are diverse and nonspecific, because the adrenals affect every system in the body. But some of the more common symptoms are:

• Fatigue
• Headaches
• Decreased immunity
• Difficulty falling asleep, staying asleep and waking up
• Mood swings
• Sugar and caffeine cravings
• Irritability or lightheadedness between meals
• Eating to relieve fatigue
• Dizziness when moving from sitting or lying to standing
• Gastric ulcers

Weak adrenals can cause hypothyroid symptoms without any problem in the thyroid gland itself. In such cases, treating the thyroid is both unnecessary and ineffective, and addressing the adrenals themselves is the key to improving thyroid function.

The most significant indirect effect the adrenals have on thyroid function is via their influence on blood sugar. High or low cortisol – caused by any of the chronic stressors listed above – can cause hypoglycemica, hyperglycemia or both. And as we saw in a previous article, blood sugar imbalances cause hypothyroid symptoms in a variety of ways.

But adrenal stress also has more direct impacts on thyroid function. The following five mechanisms are the most important.

1) Adrenal stress disrupts the HPA axis

By now many people have heard of the hypothalamic-pituitary-adrenal (HPA) axis. It’s a complex network of interactions between the hypothalamus, the pituitary and the adrenal glands that regulates things such as temperature, digestion, immune system, mood, sexuality and energy usage – in addition to controlling the body’s reaction to stress and trauma.

Countless studies show that chronic adrenal stress depresses hypothalamic and pituitary function. And since these two organs direct thyroid hormone production, anything that disrupts the HPA axis will also suppress thyroid function.

Studies have shown that the inflammatory cytokines IL-1 beta, IL-6 and TNF-alpha, which are released during the stress response, down-regulate the HPA axis and reduce levels of thyroid stimulating hormone (TSH). Another study showed that one single injection of tumor necrosis factor alpha (TNF-alpha), an inflammatory peptide, reduced serum TSH, T3, free T4, free T3 and hypothalamic TRH for 5 days. TNF-alpha was also found to decrease the conversion of T4 to T3, reduce thyroid hormone uptake, and decrease the sensitivity of the thyroid to TSH.

2) Adrenal stress reduces conversion of T4 to T3

We discussed under-conversion of T4 to T3 in a prior article. Remember that although 93% of the hormone produced by the thyroid gland is T4, it is inactive in that form and must be converted into T3 before it can be used by the cells. The inflammatory cytokines I listed above not only disrupt the HPA axis, they also interfere with the conversion of T4 to T3.

The enzyme 5′-deiodinase catalyzes the conversion of T4 into T3 in peripheral tissues such as the liver and the gut. Both Th1 and Th2 inflammatory cytokines – IL-6, TNF-alpha, IFN-gamma and IL-1 beta – have been shown to suppress the conversion of T4 to T3. In patients without thyroid illness, as levels of IL-6 (a marker for inflammation) rise, levels of serum T3 fall. And injections of inflammatory cytokines into healthy human subjects resulted in a rapid reduction of serum T3 and TSH levels, and an increase in the inactive reverse T3 (rT3) form, while T4 and free T4 levels were only minimally changed.

3) Adrenal stress promotes autoimmunity by weakening immune barriers

The GI tract, lungs and the blood-brain barrier are the primary immune barriers in the body. They prevent foreign substances from entering the bloodstream and the brain. Adrenal stress weakens these barriers, weakens the immune system in general, and promotes poor immune system regulation.

As we discussed in my previous article on the gut-thyroid connection, when these immune barriers are breached large proteins and other antigens are able to pass into the bloodstream or brain where they don’t belong. If this happens repeatedly, the immune system gets thrown out of whack and we become more prone to autoimmune diseases – such as Hashimoto’s.

4) Adrenal stress causes thyroid hormone resistance

In order for thyroid hormone circulating in blood to have a physiological effect, it must first activate receptors on cells. Inflammatory cytokines have been shown to suppress thyroid receptor site sensitivity.

If you’re familiar with insulin resistance, where the cells gradually lose their sensitivity to insulin, this is a similar pattern. It’s as if the thyroid hormone is knocking on the cell’s door, but the cells don’t answer.

While there’s no practical way to measure receptor site sensitivity in a clinical setting, the research above suggests it is decreased in autoimmune and other inflammatory conditions. A perfect example of this in practice is the Hashimoto’s patient who is taking replacement hormones but still suffers from hypothyroid symptoms – often in spite of repeated changes in the dose and type of medication. In these patients, inflammation is depressing thyroid receptor site sensitivity and producing hypothyroid symptoms, even though lab markers like TSH, T4 and T3 may be normal.

5) Adrenal stress causes hormonal imbalances

Cortisol is one of the hormones released by the adrenals during the stress response. Prolonged cortisol elevations, caused by chronic stress, decrease the liver’s ability to clear excess estrogens from the blood. Excess estrogen increases levels of thyroid binding globulin (TBG), the proteins that thyroid hormone is attached to as it’s transported through the body.

When thyroid hormone is bound to TBG, it is inactive. It must be cleaved from TBG to become “free-fraction” before it can activate cellular receptors. (These free-fraction thyroid hormones are represented on lab tests as “free T4 [FT4]” and “free T3 [FT3]“.)

When TBG levels are high, the percentage of free thyroid hormones drops. This shows up on labs as low T3 uptake and low free T4/T3.

Aside from adrenal stress, the most common causes of elevated TBG secondary to excess estrogen are birth control pills and estrogen replacement (i.e. Premarin).

Balancing the adrenals

Here’s the tricky thing about adrenal stress: it’s almost always caused – at least in part – by something else. These causes include anemia, blood sugar swings, gut inflammation, food intolerances (especially gluten), essential fatty acid deficiencies, environmental toxins, and of course, chronic emotional and psychological stress.

When they exist, these conditions must be addressed or any attempt to support the adrenals directly will either fail or be only partially successful. With that in mind, here are some general guidelines for adrenal health:

• Avoid or at least greatly minimize stimulants
• Stabilize blood sugar (via a moderate or low-carb diet)
• Practice stress management and relaxation techniques
• Have fun, laugh and make pleasure a regular part of your life
• Avoid dietary causes of inflammation (refined flours, high-fructose corn syrup and industrial seed oils in particular)
• Ensure adequate intake of DHA & EPA

Specific nutrients such as phosphatidyl serine and adaptogenic botanicals like Panax ginseng, Siberian ginseng, Ashwagandha and Holy basil leaf extract are also helpful in modulating the stress response and supporting the adrenals. However, these are potent medicines and should be taken under the supervision of a trained practitioner.

Hippocrates said: “All disease begins in the gut.” 2,500 years later we’re just beginning to understand how right he was. And, as I’ll explain in this article, hypothyroidism is no exception. Poor gut health can suppress thyroid function and trigger Hashimoto’s disease, and low thyroid function can lead to an inflamed and leaky gut – as illustrated in the following diagram:

The gut-thyroid-immune connection

Have you ever considered the fact that the contents of the gut are outside the body? The gut is a hollow tube that passes from the mouth to the anus. Anything that goes in the mouth and isn’t digested will pass right out the other end. This is, in fact, one of the most important functions of the gut: to prevent foreign substances from entering the body.

Another important function of the gut is to host 70% of the immune tissue in the body. This portion of the immune system is collectively referred to as GALT, or gut-associated lymphoid tissue. The GALT comprises several types of lymphoid tissues that store immune cells, such as T & B lymphocytes, that carry out attacks and produce antibodies against antigens, molecules recognized by the immune system as potential threats.

Problems occur when either of these protective functions of the gut are compromised. When the intestinal barrier becomes permeable (i.e. “leaky gut syndrome”), large protein molecules escape into the bloodstream. Since these proteins don’t belong outside of the gut, the body mounts an immune response and attacks them. Studies show that these attacks play a role in the development of autoimmune diseases like Hashimoto’s.

We also know that thyroid hormones strongly influence the tight junctions in the stomach and small intestine. These tight junctions are closely associated areas of two cells whose membranes join together to form the impermeable barrier of the gut. T3 and T4 have been shown to protect gut mucosal lining from stress induced ulcer formation. In another study, endoscopic examination of gastric ulcers found low T3, low T4 and abnormal levels of reverse T3.

Likewise, thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) both influence the development of the GALT. T4 prevents over-expression of intestinal intraepithelial lymphocytes (IEL), which in turn causes inflammation in the gut.

The gut-bacteria-thyroid connection

One little known role of the gut bacteria is to assist in converting inactive T4 into the active form of thyroid hormone, T3. About 20 percent of T4 is converted to T3 in the GI tract, in the forms of T3 sulfate (T3S) and triidothyroacetic acid (T3AC). The conversion of T3S and T3AC into active T3 requires an enzyme called intestinal sulfatase.

Where does intestinal sulfatase come from? You guessed it: healthy gut bacteria. Intestinal dysbiosis, an imbalance between pathogenic and beneficial bacteria in the gut, significantly reduces the conversion of T3S and T3AC to T3. This is one reason why people with poor gut function may have thyroid symptoms but normal lab results.

Inflammation in the gut also reduces T3 by raising cortisol. Cortisol decreases active T3 levels while increasing levels of inactive T3. ¹

Studies have also shown that cell walls of intestinal bacteria, called lipopolysaccharides (LPS), negatively effect thyroid metabolism in several ways. LPS:

• reduce thyroid hormone levels;
• dull thyroid hormone receptor sites;
• increase amounts of inactive T3;
• decrease TSH; and
• promote autoimmune thyroid disease (AITD).

Other gut-thyroid connections

Hypochlorhydria, or low stomach acid, increases intestinal permeability, inflammation and infection (for more on this, see my series on acid reflux & GERD). Studies have shown a strong association between atrophic body gastritis, a condition related to hypochlorhydria, and autoimmune thyroid disease.

Constipation can impair hormone clearance and cause elevations in estrogen, which in turn raises thyroid-binding globulin (TBG) levels and decreases the amount of free thyroid hormones available to the body. On the other hand, low thyroid function slows transit time, causing constipation and increasing inflammation, infections and malabsorption.

Finally, a sluggish gall bladder interferes with proper liver detoxification and prevents hormones from being cleared from the body, and hypothyroidism impairs GB function by reducing bile flow.

Healing the gut-thyroid axis

All of these connections make it clear that you can’t have a healthy gut without a healthy thyroid, and you can’t have a healthy thyroid without a healthy gut. To restore proper function of the gut-thyroid axis, both must be addressed simultaneously.

Healing the gut is a huge topic that can’t be covered adequately in a few short sentences. But I will say this: the first step is always to figure out what’s causing the gut dysfunction. As we’ve reviewed in this article, low thyroid is one possible cause, but often hypochlorhydria, infections, dysbiosis, food intolerances (especially gluten), stress and other factors play an even more significant role. The second step is to address these factors and remove any potential triggers. The third step is to restore the integrity of the gut barrier. My preferred approach for this last step is the GAPS diet.

The influence of thyroid hormones on the gut is one of many reasons why I recommend that people with persistently high TSH and low T4 and T3 take replacement hormones. Low thyroid hormones make it difficult to heal the gut, and an inflamed and leaky gut contributes to just about every disease there is, including hypothyroidism. Fixing the gut is often the first – and most important – step I take with my patients.

According to the American Association of Clinical Endocrinologists, 27 million Americans suffer from thyroid dysfunction – half of whom go undiagnosed. Subclinical hypothyroidism, a condition in which TSH is elevated but free T4 is normal, may affect an additional 24 million Americans. Taken together, more than 50 million Americans are affected by some form of thyroid disorder.

Metabolic syndrome (MetS), also affects 50 million Americans, and insulin resistance, one of the components of metabolic syndrome, affects up to 105 million Americans. That’s 35% of the population. Metabolic syndrome has become so common that it’s predicted to eventually bankrupt our healthcare system. Both metabolic syndrome and insulin resistance are risk factors for heart disease and diabetes, two of the leading causes of death in the developed world.

With such a high prevalence of both thyroid dysfunction and metabolic syndrome, you might suspect there’s a connection between the two. And you’d be right.

Studies show an increased frequency of thyroid disorders in diabetics, and a higher prevalence of obesity and metabolic syndrome in people with thyroid disorders.

That’s because healthy thyroid function depends on keeping your blood sugar in a normal range, and keeping your blood sugar in a normal range depends on healthy thyroid function.

How high blood sugar affects the thyroid

Metabolic syndrome is defined as a group of metabolic risk factors appearing together, including:

• abdominal obesity;
• high cholesterol and triglycerides;
• high blood pressure;
• insulin resistance;
• tendency to form blood clots; and,
• inflammation.

Metabolic syndrome is caused by chronic hyperglycemia (high blood sugar). Chronic hyperglycemia is caused by eating too many carbohydrates. Therefore, metabolic syndrome could more simply be called “excess carbohydrate disease”. In fact, some researchers have gone as far as defining metabolic syndrome as “those physiologic markers that respond to reduction in dietary carbohydrate.”

When you eat too many carbs, the pancreas secretes insulin to move excess glucose from the blood into the cells where glucose is used to produce energy. But over time, the cells lose the ability to respond to insulin. It’s as if insulin is knocking on the door, but the cells can’t hear it. The pancreas responds by pumping out even more insulin (knocking louder) in an effort to get glucose into the cells, and this eventually causes insulin resistance.

Studies have shown that the repeated insulin surges common in insulin resistance increase the destruction of the thyroid gland in people with autoimmune thyroid disease. As the thyroid gland is destroyed, thyroid hormone production falls.

How low blood sugar affects the thyroid

But just as high blood sugar can weaken thyroid function, chronically low blood sugar can also cause problems.

Your body is genetically programmed to recognize low blood sugar as a threat to survival. Severe or prolonged hypoglycemia can cause seizures, coma, and death. When your blood sugar levels drop below normal, your adrenal glands respond by secreting a hormone called cortisol. Cortisol then tells the liver to produce more glucose, bringing blood sugar levels back to normal.

The problem is that cortisol (along with epinephrine) is also a sympathetic nervous system hormone involved in the “flight or fight” response. This response includes an increase in heart rate and lung action and an increase in blood flow to skeletal muscles to help us defend against or flee from danger. Cortisol’s role is to increase the amount of glucose available to the brain, enhance tissue repair, and curb functions – like digestion, growth and reproduction – that are nonessential or even detrimental in a fight or flight situation.

Unfortunately for hypoglycemics, repeated cortisol release caused by episodes of low blood sugar suppresses pituitary function. And as I showed in a previous article, without proper pituitary function, your thyroid can’t function properly.

Together, hyperglycemia and hypoglycemia are referred to as dysglycemia. Dysglycemia weakens and inflames the gut, lungs and brain, imbalances hormone levels, exhausts the adrenal glands, disrupts detoxification pathways, and impairs overall metabolism. Each of these effects significantly weakens thyroid function. As long as you have dysglycemia, whatever you do to fix your thyroid isn’t going to work.

How low thyroid function affects blood sugar

We’ve seen now how both high and low blood sugar cause thyroid dysfunction. On the other hand, low thyroid function can cause dysglycemia and metabolic syndrome through a variety of mechanisms:

• it slows the rate of glucose uptake by cells;
• it decreases rate of glucose absorption in the gut;
• it slows response of insulin to elevated blood sugar; and,
• it slows the clearance of insulin from the blood.

These mechanisms present clinically as hypoglycemia. When you’re hypothyroid, your cells aren’t very sensitive to glucose. So although you may have normal levels of glucose in your blood, you’ll have the symptoms of hypoglycemia (fatigue, headache, hunger, irritability, etc.). And since your cells aren’t getting the glucose they need, your adrenals will release cortisol to increase the amount of glucose available to them. This causes a chronic stress response, as I described above, that suppresses thyroid function.

How to keep your blood sugar in a healthy range

It’s important to understand that whether you have high or low blood sugar, you probably have some degree of insulin resistance. I described how high blood sugar causes insulin resistance above. But insulin resistance can also cause low blood sugar. This condition, called reactive hypoglycemia, occurs when the body secretes excess insulin in response to a high carbohydrate meal – causing blood sugar levels to drop below normal.

In either case, the solution is to make sure your blood sugar stays within a healthy range. There are two targets to consider. The first is fasting blood glucose, which is a measure of your blood sugar first thing in the morning before eating or drinking anything. I define the normal range for fasting blood glucose as 75 – 95 mg/dL. Although 100 is often considered the cutoff for normal, studies have shown that fasting blood sugar levels in the mid-90s were predictive of future diabetes a decade later. And although 80 mg/dL is often defined as the cutoff on the low end, plenty of healthy people have fasting blood sugar in the mid-to-high 70s (especially if they follow a low-carb diet).

The second, and much more important, target is post-prandial blood glucose. This is a measure of your blood sugar 1-2 hours after a meal. Several studies have shown that post-prandial blood glucose is the most accurate predictor of future diabetic complications and is the first marker (before fasting blood glucose and Hb1Ac) to indicate dysglycemia.

Normal post-prandial blood sugar one to two hours after a meal is 120 mg/dL. Most normal people are under 100 mg/dL two hours after a meal.

Now that we know the targets, let’s look at how to meet them. If you’re hypoglycemic, your challenge is to keep your blood sugar above 75 throughout the day. The best way to do this is to eat a low-to-moderate carbohydrate diet (to prevent the blood sugar fluctuations I described above), and to eat frequent, small meals every 2-3 hours (to ensure a continuous supply of energy to the body.

If you’re hyperglycemic, your challenge is to keep your blood sugar below 120 two hours after a meal. The only way you’re going to be able to do this is to restrict carbohydrates. But how low-carb do you need to go? The answer is different for everyone. You figure your own carbohydrate tolerance by buying a blood glucose meter and testing your blood sugar after various meals. If you’ve eaten too many carbs, your blood sugar will remain above 120 mg/dL two hours after your meal.

I highly recommend you pick up a blood glucose meter if you have a thyroid and/or blood sugar problem. It’s the simplest and most cost-effective way to figure out how much carbohydrate is safe for you to eat. There are tons of meters out there, but one that gets a lot of good recommendations is the ReliOn Ultima. It’s pretty cheap, and the test strips are also cheap, which is where the major expense lies.

Finally, if you have poor thyroid function it’s important that you take steps to normalize it. As I’ve described in this article, the cycle works in both direction. Dysglycemia can depress thyroid function, but thyroid disorders can cause dysglycemia and predispose you to insulin resistance and metabolic syndrome.