+100%-

This is the third of a series of posts on non-thyroidal illness syndrome, NTIS – a pattern of altered thyroid hormone activity often present in severe trauma and critical illness. A recent study suggests NTIS may be present in chronic fatigue syndrome (ME/CFS) as well (Ruiz-Núñez et al., 2018).  Dominic provides more evidence for a potential link between the two syndromes when he shows that two factors which studies suggest play a role in ME/CFS (oxidative stress and cytokines), appear to be responsible for maintaining prolonged or chronic NTIS as well. The treatments trialed in ME/CFS and prolonged NTIS are also similar. 

Note! This is a long and technical post – you may want to print it out. 

Summary

Researchers describe a “vicious circle” involving cytokines, oxidative stress and reduced thyroid hormone activity to explain chronic “non-thyroidal illness syndrome” (NTIS) – a condition that can occur in response to virtually any severe infection, trauma, illness or surgical stress.

 

Similar patterns found in ME/CFS suggest that the five decades of NTIS research may be able to inform our understanding of the mechanisms underlying ME/CFS as well.  

 

Furthermore, the treatments trialed for NTIS are also similar to those suggested by some ME/CFS practitioners. They include supplementation with thyroid hormones, administration of hypothalamic releasing factors, supplementation with anti-oxidants, and modulation of the immune system.

Introduction

When I was researching what could improve my wife’s debilitating condition, I found that most ME/CFS practitioners treat the immune system, some address the action of thyroid hormones, and a few practitioners target both the immune system and thyroid hormones (see my previous blog post). Dr Sarah Myhill, for example, believes immunological issues largely underlie ME/CFS, but also describes the complete recovery of patients using thyroid hormone supplementation (Myhill, 2018).

NTIS critical illnesses

NTIS is a pattern of altered thyroid hormone activity that can occur in response to virtually any severe infection, trauma, illness or surgical stress

This made me interested in understanding the relationship between the immune system and the action of thyroid hormones at the cellular level. I was particularly interested in learning if the relationship between the immune system and thyroid hormones could produce a feedback loop that leads to a patient becoming “stuck” in an ME/CFS-like illness state.

I found that the relationship between inflammation and thyroid hormone activity has been studied for decades and continues to be studied in the context of a condition called “non-thyroidal illness syndrome” (NTIS) – also called “euthyroid sick syndrome” or “low T3 syndrome” – often present in severe trauma, critical illness and following surgeries. Moreover, I learnt that some of the more recent NTIS research describes “vicious circles” mediated by cytokines, oxidative stress and thyroid hormone activity that keep some patients ill in a form of “prolonged” or “chronic” NTIS (Mancini et al., 2016; Chatzitomaris et al., 2017).

Furthermore, to my surprise, there are many physiological similarities between ME/CFS and NTIS, including: down-regulation of metabolism, reduced mitochondrial activity, oxidative stress, distinct cytokine signatures, altered immune cell activity, dysregulation of adrenal hormones, etc. (see Table 1 at the end of the blog post).

In this post, I will argue that the findings stemming from five decades of NTIS research will likely provide important insights into the mechanisms underlying ME/CFS.

First, I provide an overview of some of the mechanisms described in the literature on NTIS, specifically the “vicious circle” described by some researchers (Section 1). Secondly, I summarize some of the main implications of increased cytokines and oxidative stress level, and depressed thyroid hormone activity — and similarities with ME/CFS (Section 2). Finally, in view of their potential application for ME/CFS, I briefly present the ongoing debates regarding NTIS treatment (Section 3).

Although this blog post is focused on the mechanisms related to alterations in thyroid hormone activity, it’s important to note that other endocrine systems are also altered in trauma and critical illness, specifically the growth hormone and adrenocorticol axes (van den Berghe, 2016). Research in the field of critical care medicine on these endocrine systems and other aspects of critical illness (see Annex) may also be relevant for understanding the mechanisms of ME/CFS but are beyond the scope of this blog post.

Section 1: Mechanisms in NTIS

Starting in the early 1970s, clinicians working in intensive care units observed that patients with a wide range of critical conditions – starvation, severe burns, head injuries, sepsis, heart surgery, renal failure, etc. – had low plasma concentrations of the active form of thyroid hormones (T3), and high plasma concentrations of inactivated thyroid hormones (reverse T3; rT3) (Warner and Beckett. 2010).

Over time, it became clear that this pattern of altered thyroid hormone concentrations can occur in response to virtually any severe infection, trauma, illness or surgical stress (De Groot, 1999; Wajner et al., 2012). Clinicians gave this condition the name “non-thyroidal illness syndrome” (NTIS), also called “euthyroid sick syndrome” or “low T3 syndrome.”

Recognizing that thyroid hormones regulate the rate of our metabolism, NTIS was initially described as a state of “protective” down-regulation of metabolism during times of duress – i.e. a form of “hypometabolism” to save energy (Carter et al. 1974).

However, the initial assumption that NTIS is a “protective” down-regulation of metabolism is increasingly being questioned by NTIS researchers – particularly in the case of chronic or prolonged rather than acute or transitory cases of NTIS (Boelen, 2011; van den Berghe, 2016).

As the mechanisms involved in NTIS were elucidated, researchers increasingly began to suggest that chronic NTIS was a “maladaptive process.” Irrespective of the initial illness or trigger, some patients appeared to get stuck in a chronic, hypometabolic state they had difficulty escaping from (Plikat et al., 2007).

Based on nearly five decades of NTIS and related studies, researchers have proposed a model that describes how the vicious circle which keeps some people stuck in a prolonged or chronic state of NTIS occurs. This model suggests that this hypometabolic state is maintained by reciprocal relationships between inflammatory cytokines, reduced thyroid hormone activity, and oxidative stress (Mancini et al., 2016; Chatzitomaris et al., 2017).

Figure 1: Simplified model of NTIS, based on the paper by Mancini, et al. 2016 (see the paper for the more complex model).

Figure 1: First thought to be protective mechanism brought on by severe illness, prolonged NTIS is now thought to be a maladaptive response occurring when cytokines and oxidative stress impact thyroid hormone activity

This simple model doesn’t address all aspects of NTIS, nor does it incorporate the associated changes in other endocrine systems during critical illness (such as the adrenal hormone system), but it does serve as a good introduction to the bulk of the literature on NTIS.

The key elements of this suggested “vicious circle” in prolonged NTIS include the following mechanisms:

  1. cytokines depress thyroid hormone activity;
  2. low thyroid hormone activity contributes to oxidative stress; and
  3. oxidative stress stimulates the production of pro-inflammatory cytokines – thereby completing the circle.

I will explain these mechanisms in detail in the next three sub-sections.

Mechanism #1: Cytokines depress thyroid hormone activity

Cytokines: Cytokines are low-molecular-weight proteins that regulate the nature, intensity and duration of the immune response and play important roles in autoimmune and inflammatory diseases. Very versatile, cytokines can act in an autocrine (affect the same cell), paracrine (affect cells close to them) or endocrine (affect cells far away) fashion and can affect different cells in different ways. In what’s called a cascade effect, cytokines often stimulate the production of other cytokines. Over 50 cytokines and chemokines exist.

In trying to understand the mechanisms behind NTIS, researchers followed up on a major clue: the fact that alterations in activated (T3) and inactivated (rT3) thyroid hormone concentrations in plasma are associated with alterations in cytokine levels as well (Boelen et al., 1993; Davies et al., 1996; Maura Neto et al., 2016).

In the past few decades researchers have increasingly clarified the ways in which cytokines depress thyroid hormone activity. These can be categorized into sub-mechanisms at (i) “central level” (i.e. “above the neck”) and (ii) “peripheral level” (i.e. “below the neck.”).

I will give a brief overview of these sub-mechanisms in the paragraphs below. However, two key take-aways from this process are:

First, these sub-mechanisms result in tissue-specific down-regulation of metabolism. Interestingly, the metabolism of different tissues (the liver, kidney, brain, heart, adipose tissue, and other tissues) is down-regulated at different rates, perhaps in order of the importance of the organs to survival.

Second, by just looking at the concentrations of activated and inactivated thyroid hormone in the plasma (as is usually the case in clinical settings), we only see the “tip of the iceberg” of the alterations in thyroid hormone activity occurring at the tissue level (Ruiz – Nunez et al., 2018; Donzelli et al., 2016). In fact, the tissue-level alterations in thyroid hormone are often easily missed all together (Dietrich et al., 2016).

(a) “Central level”: how cytokines depress the overall production of thyroid hormones

In chronic NTIS, cytokines targeting the hypothalamus (located in the middle of the brain), the pituitary (located at the front of the brain) and the thyroid glands (located in the neck) can lead to a reduction in the overall production of thyroid hormones.

Under normal conditions, a thyroid hormone feedback system works like a thermostat to maintain stable plasma thyroid hormone concentrations according to a daily rhythm (Fisher, 1996). In brief, when activated thyroid hormone concentrations in the plasma dip below a certain threshold, the hypothalamus produces thyrotropin-releasing hormones (TRH) in order to signal the pituitary to produce thyroid stimulating hormone (TSH), which in turn signals the thyroid gland to produce more thyroid hormone (TH).

Figure 2: The cascade for production of thyroid hormone (TH)

However, in the case of chronic NTIS, cytokines (e.g. IL-12 and IL-18), in association with other signaling factors (including leptin, glucocorticoids, etc.), inhibit the production of TRH by the hypothalamus (Boelen et al. 2004; Chatzitomaris et al., 2017).

It’s believed they do this by “up-regulating” the deiodinase enzymes D1 and D2 which convert the mostly inactive form of thyroid hormone (T4) into the active form (T3) in the hypothalamus. The increased local T3 levels then give the hypothalamus the “impression” that active hormone levels are fine (Joseph-Bravo et al., 2015). It is as if the air around the thermostat was being heated, making it appear the house is warm enough.

As a result, in chronic NTIS plasma thyroid hormone levels have to drop a lot more than usual in order for the hypothalamus to initiate the sequence that (via TRH and TSH) results in the production of more thyroid hormone by the thyroid gland. Researchers call this an alteration in the “set point” of the feedback mechanism between the plasma concentration of T3 and the release of TRH (Chatzitomaris et al., 2017).  (Note: this phenomenon also explains why TSH levels can appear normal in blood tests even when plasma thyroid hormone levels are low.)

Moreover, without going into details, in a process called “TSH suppression”, cytokines (e.g. IL-1b and TNF-α) also decrease the release of TSH by the pituitary (Harel et al., 1995; Wassen et al. 1996). Finally, by reducing iodine uptake and thyroid hormone excretion, cytokines (e.g. IL-1) also impact the activity of the thyroid gland itself (Bartelena, 1998; De Groot 1999).

The consequence of these “central” mechanisms – i.e. the alteration of the “set-point” for TRH production, the “TSH suppression”, and/or the inhibition of the thyroid gland – is a general depression in plasma thyroid hormones leading to generalized hypo-metabolism.

It should be noted that these “central” mechanisms come into play during prolonged or chronic NTIS. During acute and early stages of NTIS, “peripheral” mechanisms serve to down-regulate metabolism quickly to help conserve energy resources (Wajner et al. 2012; van den Berghe, 2014). I will explain these mechanisms next.

(b) “Peripheral level”: how cytokines depress thyroid hormone activity in tissue-specific ways

In acute and early stages of NTIS, mechanisms involving cytokines lead to the quick depression of thyroid hormone activity in tissue-specific ways.

Under normal conditions, once thyroid hormones are released by the thyroid gland into the plasma, further steps need to be completed before they can impact the metabolism of the target tissue. Simply put:

  1. thyroid hormones are first “bound” to thyroid hormone binders and carried around the body;
  2. cellular transporters then “transport” the thyroid hormones into the cells;
  3. inside the cells, deiodinase enzymes “convert” thyroid hormones into the active or inactive forms;
  4. when the active thyroid hormone is then “received” by nuclear receptors, the target cells initiate gene transcription. (Alternatively, gene transcription is halted if an inactivated form of thyroid hormone (rT3) lodges onto the nuclear receptors).

(Note: thyroid hormones can also interact with other elements in the cells to initiate “non-genomic” effects).

An alteration in any of these steps can lead to large “time and tissue-specific” adjustments in cellular metabolism – even without any, or only minor, changes in the plasma concentrations of thyroid hormones (Gereben et al., 2008; Mendoza et al., 2017; Cicatiello et al., 2018).

Figure 3: The path of the thyroid hormones to target tissues

NTIS researchers have shown that cytokines (notably IL-1β, IL-6, TNF-⍺) can impact each of these steps (see review by Warner and Beckett, 2010; Wajner et al., 2012).

Alterations induced by cytokines on the path of the thyroid hormones include:

  • changes in the amount and affinity of thyroid hormone binders in the blood (Bartelena et al., 1992; Bartelena et al., 1998; Afandi et al., 2000);
  • modifications in the expression of the transporters that bring the thyroid hormone into the cells (Mebis et al., 2009);
  • the down– and up-regulation of deiodinase enzymes that convert the thyroid hormone into active and inactive forms, respectively (Bartalena et al., 1998; Huang et al., 2005);
  • the variation in the quantity and type (i.e. “isoforms”) of cellular thyroid hormone receptors present (Kwakkel et al., 2007; Rodriguez-Perez et al., 2008; Lado-Abeal et al., 2010).

The relative sequence and importance of these various “peripheral” mechanisms in depressing thyroid hormone activity in different phases of NTIS and different tissues are the subject of most NTIS publications (see the reviews of Warner and Beckett, 2010; Wajner et al., 2012; and Chatzitomaris et al., 2017). (Note: additional mechanisms have also been proposed; see Annex).

Of the above mechanisms, the ones that have received the most attention are the effect cytokines have on the down-regulation of the deiodinase enzymes that convert thyroid hormones into the active form T3 and the up-regulation of the enzymes that convert thyroid hormones into the inactivated form “reverse T3” (rT3).

Notwithstanding the differences found between the tissues, and between acute and prolonged NTIS (Mebis et al., 2007; Boelen et al., 2017; Fontes et al., 2017), alterations in the activity of the deiodinase enzymes during NTIS generally lead to a decrease in the active form of thyroid hormone (T3) and an increase in the inactivated form (rT3) in peripheral tissues. This explains the alternative name for the syndrome: “low T3 syndrome.”

In sum: the various “central” and “peripheral” level sub-mechanisms induced or maintained by cytokines during prolonged NTIS result in a general and tissue-specific reduction of thyroid hormone activity – in other words: hypo-metabolism. Moreover, the observed changes in the plasma concentrations of thyroid hormones are just a fraction of the mostly invisible changes in thyroid hormone activity experienced at the level of the tissues (i.e. are “the tip of the iceberg”).

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Mechanism #2: Depressed thyroid hormone activity contributes to oxidative stress

Oxidative stress is the imbalance between the production of pro-oxidant substances and anti-oxidant defenses. In other words, oxidative stress occurs when there are not enough anti-oxidants to neutralize the pro-oxidants in the body. The most important pro-oxidants are the reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS are formed as natural byproducts of the normal metabolism of oxygen (c.f. mitochondrial respiratory chain) and enzyme activity, respectively. Enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as transition-metal binding proteins such as transferrin, ferritin, and ceruloplasmin, prevent the production of pro-oxidants or rapidly inactivate them. Sources: Mancini et al., 2016, and Wikipedia

As described above, researchers have established that through a number of mechanisms, thyroid hormone activity is depressed during NTIS via the mediation of cytokines. This brings us to the second key element of the “vicious circle” in chronic NTIS: low thyroid hormone activity contributes to oxidative (and nitrosative) stress.

Both hypothyroidism and hyperthyroidism have long been associated with oxidative stress (Canon-Europa et al., 2012). In the case of hypothyroidism, the principal mechanism is the inability of the cells to make sufficient anti-oxidants to maintain a healthy oxidative balance. (In the case of hyperthyroidism, the mechanism is the generation of too many pro-oxidants.)

The same mechanism existing with hypothyroidism is at work in the case of NTIS. Specifically, the depressed thyroid hormone activity results in reduced function of two proteins (“Uncoupling Proteins-2 and -3”) with anti-oxidant properties (Bianco et al., 1988). In addition, low cellular thyroid hormone levels alter the lipid concentration of the cell membranes which in normal conditions maintain the cells’ oxidative balance. Finally, as a result of low thyroid hormone activity the mitochondria which have been damaged by oxidative stress are not cleared out (cited in Mancini et al., 2016). In sum, during times of low thyroid hormone activity, intra-cellular oxidative stress increases.

In turn, oxidative stress inhibits thyroid hormone activity via competition for glutathione (GSH) by both anti-oxidant enzymes and the above mentioned deiodinase enzymes (Wajner et al., 2012).  Researchers believe that oxidative stress “depletes the glutathione” required for the conversion of T4 into T3, resulting in lower concentrations of active thyroid hormones.

Similarly, NTIS researchers hypothesize that the competition for and the resulting depletion of the trace mineral selenium – a component of both the deiodinase and the anti-oxidant enzymes (Wajner et al., 2015) – may amplify the link between increased oxidative stress and low thyroid hormone activity.

In sum, in the event of low thyroid hormone activity, the body is unable to make enough anti-oxidants to counteract the pro-oxidants. This leads to increased oxidative stress, which tends to depress the activity of thyroid hormones further, due to competition for glutathione and selenium in a self-perpetuating cycle (i.e. a smaller “vicious circle” is present within the larger one).

Mechanism #3: Oxidative stress stimulates pro-inflammatory cytokines

The final mechanism which completes the “vicious circle” in chronic NTIS is the link between oxidative stress and inflammation.

Oxidative stress stimulates the production of inflammatory cytokines, notably leptin, resistin, TNF-α, and IL-6 (Chatterjee, 2016).

In turn, inflammatory cytokines (notably IL-6) further increase oxidative stress by triggering the production of superoxide radicals (Valko et al., 2007; Wajner et al., 2012).

In sum, oxidative stress triggers the release of additional inflammatory cytokines which reduce thyroid hormone activity – leading to more oxidative stress. There is thus a tendency for oxidative stress and pro-inflammatory cytokines to perpetuate each other (i.e. forming yet another smaller “vicious circle” within the larger one).

Section 2: Implications of NTIS and similarities with ME/CFS

In Section 1, I provided an overview of the key mechanisms of the “vicious circle” which underpins chronic NTIS following trauma and critical illness as described by NTIS researchers:

  1. cytokines depress thyroid hormone activity;
  2. low thyroid hormone activity increases oxidative stress;
  3. increased oxidative stress stimulates the production of pro-inflammatory cytokines … which perpetuates the “vicious circle.”

Moreover, the research indicates that there are arrows cutting across the “vicious circle” as well.  Reciprocal relationships exist between thyroid hormone status and oxidative stress; between oxidative stress and inflammation; and between oxidative stress and thyroid hormone activity. These smaller “vicious circles” within the elements of the larger “vicious circle” in chronic NTIS appear to make it even harder for patients to escape from the trap.

In the next paragraphs I will describe the implication of these mechanisms and highlight similarities with ME/CFS, in order to argue that the NTIS research can likely inform our understanding of the mechanisms underlying ME/CFS.

Implications of oxidative stress

The implications of chronic oxidative stress in the body are widely documented. Oxidative stress causes cell damage and disrupts normal cellular transcription and signaling mechanisms (Mancini et al, 2016).

Numerous studies have found increased oxidative stress in ME/CFS. Oxidative stress has been identified as a factor in the metabolic dysfunction in ME/CFS (Morris and Maes, 2014; Armstrong et al., 2015). Indeed, a model which describes a “vicious circle” involving oxidative / nitrosative stress and cytokines in ME/CFS has been proposed by Prof. Martin Pall (cf. the “NO/ONOO-Cycle,” 2010). Researchers also suggest that high lactate / low glutathione levels found in the brains of people with ME/CFS likely derive from similar mechanisms involving oxidative stress (Shungu et al., 2012)

Implications of tissue specific reduced thyroid hormone activity

One implication of prolonged reduced thyroid hormone activity seen in NTIS is, of course, a down-regulation of metabolism. Metabolic studies document a similar down-regulation in ME/CFS (Naviaux et al., 2016). Moreover, reduced mitochondrial activity has been suggested in NTIS (Warner and Beckett, 2010) and observed in ME/CFS (Myhill et al., 2009; Esfandyarpour et al., 2019).

Certainly, many ME/CFS practitioners now recognize that reduced thyroid hormone activity plays a role in ME/CFS (see my previous blog post). Ruiz-Núñez’s et al. (2018) found that CFS patients had significantly lower levels of active thyroid hormone (T3) and a higher ratio of inactivated to active thyroid hormones (rT3:T3) than controls.

Moreover, one implication of a tissue-specific down-regulation of thyroid hormone activity is that some organs will work better than others. Experimenting in rats, researchers have shown that depressed thyroid hormone levels occur in a specific sequence, manifesting (from first to last) in the liver, kidney, brain, heart and adipose tissues (Donzelli et al., 2016). Some ME/CFS practitioners have argued that this tissue-specific modulation can help explain the disparate and evolving symptoms in ME/CFS and fibromyalgia (Lowe, 2000; Lowe and Yellin, 2008; Holtorf, 2014a and Holtorf 2014b).

The prolonged down-regulation of thyroid hormone activity certainly has implications for the immune system. Authors describe the profound effects of circulating thyroid hormone levels on the activity of monocytes, lymphocytes, macrophages, neutrophils, dendritic cells and natural killer cells (Balaz et al., 1980; Pillay, 1998; Klecha et al., 2005; Klein, 2006; Hodkinson, 2009; Straub et al., 2010; Jara et al., 2017; Bilal et al., 2017; Van der Spek et al., 2018). Notably, depressed thyroid levels appear to depress the activity of natural killer cells (DeVito et al., 2011) – a signature finding in ME/CFS (Klimas et al., 1990).

Implications of altered cytokine levels and suppression of endocrine axes

The alterations in cytokines found in NTIS – notably increased markers of inflammation – likely have many additional implications that have yet to be fully understood (Van der Spek et al., 2017). Here again, parallels can be drawn between NTIS and ME/CFS: distinct cytokine signatures have been found in ME/CFS (Montoya et al., 2016) and fibromyalgia (Hernandez et al., 2010).

Finally, cytokines may be a culprit in the “central” (hypothalamic or pituitary) suppression of the growth hormone and adrenocortical hormones axes in prolonged critical illness (van den Berghen, 2016) — in addition to the suppression of the thyroid hormone axis (described in this blog post). It has been shown that adrenocortical hormone axes are suppressed in ME/CFS (see review by Tomas et al., 2013). Indeed, several ME/CFS practitioners hypothesize that the central suppression of endocrine axes is an essential mechanism underlying ME/CFS (Teitelbaum, 2007; Holtorf, 2008; Purser, 2010) — perhaps it is at the heart of both ME/CFS and prolonged critical illness?

Section 3: Emerging treatments for NTIS

Based on the increasing recognition of chronic NTIS as a “maladaptive process” following trauma or critical illness, researchers have been looking for remedies that target the different elements of the “vicious circle” described in Section 1: low active thyroid hormone status, oxidative stress, and inflammation (see review in Fliers et al., 2015).

Thyroid hormone supplementation

Given the reduced thyroid hormone activity in NTIS, clinicians began, as early as the 1980s, to suggest thyroid hormone supplementation in their critical NTIS patients in an attempt to increase their survival rates (Carter et al., 1977; Brent et al., 1986 and DeGroot, 1999). This approach continues to be debated today (Davis, 2008; Kaptein et al., 2010; De Groot, 2015; De Neto et al., 2016; Breitzig et al., 2018).

Results with thyroid supplementation have been mixed (Farwell, 2008), but have most often been beneficial (see review in Fliers et al., 2015). Interestingly, positive results have reportedly been achieved by supplementing thyroid hormones in NTIS patients who had become ill after mold exposure (Somppi, 2017).

Given the impaired conversion of T4 to T3 in NTIS, some researchers also propose T3 supplementation (as opposed to T4 supplementation) (Biondi, 2014). Moreover, tests on rabbits have shown that thyroid hormone supplementation doses have to be very high to achieve results (Debavaye, 2008). These suggestions regarding the type and quantity of thyroid hormone supplementation in NTIS echo the arguments made by some practitioners on T3 supplementation for ME/CFS (see my previous blog post).

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Many publications simply conclude that more studies on the effects of thyroid hormone supplementation on tissue thyroid levels, etc. in NTIS will be required:

“Indeed, it is probable that a full understanding of the pathophysiological mechanisms at the tissue level will allow the identification of patients who would benefit from replacement therapy.” (Mancini et al., 2016).

Stimulating the hypothalamus and pituitary

Van den Berghe et al. (2002, 2014, 2016) achieved metabolic improvements using infusions of growth hormone-releasing peptide and thyrotropin-releasing hormone (TRH) in patients with protracted critical illnesses. In other words, they’ve succeeded in breaking the “vicious circle” in prolonged NTIS by stimulating the hypothalamus and pituitary to restore thyroid hormone concentrations (see “central mechanisms” in Section 1 above).

Crucially, they have, through this approach, addressed problems not just at the hypothalamus-pituitary-thyroid axis, but at other endocrine axes controlled by the hypothalamus – i.e. the hypothalamus-pituitary-growth hormone and hypothalamus-pituitary-adrenocortical axes – two axes not covered in this blog post but which are also impacted in critical illness and trauma (and work in association with the thyroid axis).

Anti-oxidant supplementation

In one case, researchers have found that treating patients of acute myocardial infarction with n­acetyl-cysteine (NAC) – a precursor to the anti-oxidant GSH – could virtually eliminate the decrease in serum T3 levels and prevent the increase in serum rT3 usually seen (Vidart et al., 2014). In other words, they seem to have broken the “vicious circle” by restoring oxidative balance via the administration of anti-oxidants. (Recall that during oxidative stress, competition for GSH by both the anti-oxidant enzymes and the deiodinase enzymes leads to deranged thyroid hormone conversion as well as increases in pro-inflammatory cytokines.)

Selenium supplementation

Research suggests that supplementation with selenium is associated with modest “normalization” of thyroid hormones in NTIS patients (Berger et al., 2001). Moreover, controlled experiments on human cells showed that the administration of sodium selenite reduces cytokine (IL-6)-induced oxidative stress, but it did not fully restore thyroid hormone conversion (Wajner et al., 2016). This implies that selenium supplementation can be helpful, but alone it is insufficient to break the “vicious circle” in NTIS. (Recall that anti-oxidant enzymes and thyroid deiodinase enzymes both contain selenium, and thus this mineral is required for their production.)

Cytokine blockers

Researchers tried to stop the vicious circle in NTIS by blocking the IL-1 cytokine receptors (via a receptor antagonist), but this did not prevent the drop in T4, free T4, T3, and TSH or the rise in rT3 caused by endotoxin (van der Poll, 1995). This result is not surprising, given that “cytokines are related to each other in a very complex network and regulate, positively or negatively, the expression of other cytokines; it is, therefore, difficult to imagine how to interrupt this interplay and cascade of events” (Bartelena, 1998). (Recall that IL-1 cytokines are involved in both central and peripheral mechanisms to reduce thyroid hormone activity.)

Immune system modulation

One interesting hypothesis suggests that “it is the immune system — not the endocrine system — that re-starts the process of thyroid hormone output” during recovery from NTIS (Klein, 2006). This hypothesis is further supported by the surprising finding that immune cells are able to produce TSH, T4 and T3 on their own (Bilal et al, 2017).

Klein writes: “The immune system, which is indeed capable of TSH production, would be well suited to determine the optimal time to initiate the thyroid hormone recovery phase. A critical factor in this would be the inherent ability of the immune system to continually assess the status of the infectious condition, and thus to determine whether or not it is safe for the host to return to a state of normal metabolic activity.”

Following this logic — and recognizing the regulatory effect thyroid hormones have on the immune system — some have suggested modulating the immune functions via clinical manipulation of thyroid hormone levels (DeVito et al., 2011). Supplementation with thyroid hormones might therefore serve in at least two ways to break the “vicious circle”: directly by increasing thyroid hormone activity, and indirectly by modulating the immune system.

In sum, the overlap in treatment attempts for ME/CFS and NTIS underlines the importance of NTIS research results also being considered in relation to ME/CFS. 

Conclusion:

Given the similarities between the profiles of ME/CFS and chronic NTIS following trauma and critical illness (see Table 1 below), the findings from five decades of NTIS research may also be relevant to understanding the mechanisms behind ME/CFS.

A defining feature of NTIS is low thyroid hormone activity, which in prolonged or chronic NTIS, is mediated by cytokines and oxidative stress through both “central” and “peripheral” mechanisms. The reduced plasma thyroid hormone levels readily observed in NTIS likely reflect just the “tip of the iceberg” of the thyroid hormone level reductions seen at the tissue level in these critical patients.

Research on chronic NTIS has elucidated the reciprocal relationships between cytokines, thyroid hormone activity and oxidative stress which suggest chronic NTIS patients may be stuck in a “vicious circle.”

The implications of the tissue-specific down-regulation of thyroid hormone activity on the body are numerous, including depressed immune system function.

NTIS researchers and clinicians looking for ways to break patients out of this “vicious circle” have used experimental treatments similar to those used by some ME/CFS practitioners. These include supplementation with thyroid hormones, administration of hypothalamic releasing factors, supplementation with anti-oxidants, and attempts to mitigate the effect of cytokines.

Additional research on trauma and critically ill patients describes a similar pattern of “central” (hypothalamic or pituitary) suppression of other endocrine systems not covered by this blog post (i.e. the hypothalamus-pituitary-growth hormone and hypothalamus-pituitary-adrenocortical axes). The suppression of endocrine axes at the central level echos the hypotheses of several ME/CFS practitioners.

Finally, I suggest that further exchanges between researchers working on ME/CFS and trauma and critical illness would likely greatly benefit both research communities in the quest for treatments for both NTIS and ME/CFS.

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The Critical Illness Series on Health Rising

Notes

Table 1: Similarities between NTIS and ME/CFS

The “bio-markers” or “signature” findings in ME/CFS described by recent studies are similar to findings in NTIS. The list of similarities highlighted in the table below is not exhaustive, but may be sufficient to suggest that the research into the mechanisms behind chronic NTIS is likely relevant to understanding the mechanisms behind ME/CFS.

Findings in ME/CFSDetails for ME/CFSSimilarities in NTIS
Altered immune cell activityKlimas et al. (1990) and many others have found reduced Natural Killer cell function in ME/CFS patients.A prolonged deficiency of thyroid hormone is related to the impairment of the cellular immune system (Pillay, 1998; Van der Spek et al., 2017) – notably reduced activity of natural killer cells (DeVito et al., 2011).
Down-regulation of metabolism

 

 

Naviaux et al. (2016) found irregularities in the metabolites of ME/CFS patients, “consistent with a hypometabolic syndrome.”NTIS is characterized by low active thyroid hormone inducing a generalized hypo-metabolic state (Warner and Beckett, 2010; Wajner et al., 2012).
Reduced mitochondrial activityMyhill et al. (2009) showed that ME/CFS patients were unable to replenish ATP stores, attributing this to reduced mitochondrial activity. See also Esfandyarpour et al. (2019).Reduced intra-cellular ATP has also been suggested as a mechanism in NTIS (Warner and Beckett, 2010).
Distinct cytokine signatures

 

Montoya et. al (2017) found that some 17 cytokines were positively correlated with the severity of ME/CFS, of which 13 are pro-inflammatory (see also Hornig et al., 2015). Similarly, circulatory levels of proinflammatory cytokines are altered in fibromyalgia patients (Hernandez et al., 2010).NTIS has long been associated with changes in cytokines (Boelen et al., 1993; Bartelena et al., 1998).
Oxidative StressME/CFS has been associated with oxidative stress (Morris and Maes, 2014; Armstrong et al., 2015).Oxidative stress is a key mechanism in NTIS (see Wajner et al., 2012; Mancini et. al, 2016 and Chatzitomaris et al., 2017).
Reduced plasma levels of active thyroid hormone; increased levels of biological inactivated thyroid hormonesRuiz-Núñez’s et al. (2018) found that, as a group, CFS patients had significantly lower “Total T3” (TT3) levels (i.e. the active form of thyroid hormones) and a higher “rT3 to total T3 ratio” (rT3:TT3) than controls – meaning a higher ratio of inactivated to active thyroid hormones. They write: “low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels.”NTIS is by definition a reduction in plasma levels of active thyroid hormone. (Chopra, 1979; Warner and Beckett, 2010). The decrease in T3/rT3 relationship is considered the most sensitive parameter for diagnosis of NTIS (Neto et al., 2016).
Dysregulation in adrenal hormonesDi Giorgio et al. (2016) have found that the hypothalamus- pituitary- adrenal axis is dysregulated in ME/CFS patients (see also: Teitelbaum, 1996; Durrant-Peatfield, 2006; Skinner, 2003, Tomas et al., 2013).“Prolonged NTIS is hallmarked by a uniform suppression of the neuroendocrine axes, predominantly of central/hypothalamic origin, which contributes to the low (or insufficiently high) circulating levels of hormones” (van den Berghe, 2016).
Various triggers Chu et al. (2019) cites the most common peri-onset events reported by subjects were infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%).NTIS occurs in response to virtually any illness or surgical stress (De Groot, 1999; Wajner et al., 2012).

 

 

 

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