Introduction
Metabolism is the consumption of energy by a living organism. Basal metabolism is basically the sum of all energy the body uses to maintain its warm internal environment (37 °C or 98.6 °F nominally) in the face of the external environment. In essence, basal metabolism is the energy required to maintain homeostasis, and nothing else. Activity (walking, thinking) is considered to consume additional energy above basal metabolism.
Basal metabolism is measured via the proxy of body temperature and is said to represent the energy used to maintain a constant internal environment, known as homeostasis. Typically basal temperature itself cannot be measured so one measures 'resting' temperature first thing in the morning. For example, part of homeostasis in animals is movement to a more optimal environment, so where do you draw the line? The difference between resting and basal temperatures is a somewhat academic dispute that mostly has to do with the fact that body temperature follows a diurnal pattern, being lower at night while sleeping and higher in the day while active. This difference is a combination of higher cortisol activity and muscle motion during the day. Typically the night-time low cortisol state is regarded as the most reasonable approximation to basal temperature. Furthermore where you measure temperature matters. Armpit temperatures will be lower than sub-lingual (under the tongue) temperatures, which in turn will be lower than rectal or vaginal temperatures. Personally, I have a waking sub-lingual temperature of 36.5-.6 °C measured by a scientific mercury thermometer, which would solidly put me in the normal category at 37 °C internal temperature.
When we are talking about whether someone has a 'fast' or 'slow' metabolic rate we are usually referring to the concentration of active thyroid hormone in the major energy-consuming tissues, and not necessarily body temperature. Although the two are correlated, they are not the same thing. This is not to say that temperature doesn't matter, however, as most of the enzymes in your body have optimal activity close to 37 °C, which is why we evolved to maintain that particular internal temperature.
The thyroid hormone triiodothyronine (T3) is a DNA transcription effector. That means that every time a cell in your body produces a messenger RNA that goes on to assemble a protein, there must be a T3 molecule bound to the DNA (typically alongside several other gene regulators). T3 is an enzyme, so it isn't destroyed by the process of transcription, but the concentration of T3 is important in determining the rate of protein synthesis. Protein synthesis is a high energy consumption activity (around 9 kcal/g), so someone with poor basal hormone levels is going to have to do something else with that unused energy (i.e. fat storage) and there will also be less waste heat generated, so overall body temperature will decrease. Regulation of T3 levels is a complicated equilibrium process and I will try to explain it concisely and clear as I'm able.
Regulation of basal metabolism can be broken down into four basic components:
- the hypothalamus/pituitary gland, which controls the negative feedback of the system and regulates the thyroid through thyrotropin (TSH);
- the thyroid gland itself, which produces thyroxine (T4);
- the deiondinase system (D1, D2, and D3), which converts T4 to the metabolically active form triiodothyronine (T3) in many diverse organs but especially the liver, skeletal muscle, the brain, and the thyroid itself, and D3 inactivates T3 to T2 in the liver;
- the transport proteins, which are produced by the liver, which regulate the reservoir of T4 and T3 found in the blood (and hence their availability to tissues over seconds/hours/days timescales).
The axis of organs which dominate regulation of basal metabolism is the hypothalamus/pituitary/thyroid/liver. So whenever you have someone who self-diagnoses "hypothyroidism" any one of the above stages in the regulatory chain could be disrupted, and not necessarily the thyroid per se. An individual with poor basal metabolism but a healthy thyroid gland is usually referred to as having
euthyroid sick syndrome, with the
eu-prefix meaning true or normal. Another common synonym is
non-thyroidal illness(es) often abbreviated NTI (
de Groot, 1999). Euthyroid sick syndrome sometimes refers specifically to problems downstream of the thyroid (i.e. the deiodinases) and non-thyroidal illness to problems upstream (hypothalamus/pituitary) but the scientific literature is not consistent.
Kohrle (2000), provides an excellent quotation that underscores the complexity of the situation in how the literature on this subject is far too often confusing and contradictory,
As discussed above, complex superimposed and mutually interacting alterations of thyroid hormone economy are observed under these conditions: stress, activation of the pituitary-adrenal axis, inhibition of thyroid hormone production and secretion, changes in serum binding and distribution, tissue uptake and intracellular metabolism. Therefore it is not at all surprising, that different cellular or animal models and experimental manipulations provoking these syndromes led to divergent results.
Nominally non-thyroidal illness is considered an acute condition that passes with time (or kills the patient, acute NTI is very dangerous) but I strongly suspect that the same mechanisms can result in chronic conditions. My objective in this article is to explore how the basal metabolic system could potentially be disrupted in a chronic fashion to address the extremely common idiopathic “sub-clinical hypothyroidism” that I see evidence of far too often. The acute form of non-thyroidal illness often features a simultaneous lowering of TSH, T4, and T3 but all these features may not be present in more chronic conditions.
Hypothalamus
The headwaters of the basal metabolism control system starts in the hypothalamus, where a number of feedback mechanisms occur. When the hypothalamus determines that basal metabolism should be raised, it releasing thyrotropin-releasing hormone (TRH). TRH modulates the release of a number of other hormones (including prolactin, oxytocin, and arginine vasopressin) but primarily it stimulates the pituitary gland to produce thyrotropin (aka thyroid-stimulating hormone, TSH).
Leptin is one hormone that strongly influences the TRH neurons in the hypothalamus (
Rogers, 2009). Individuals who were previously obese still have a greater than normal number of fat cells, with the result that circulating leptin levels are lower than one would otherwise guess from present body fat levels (
Spalding, 2008). I have previously tried to make the case that formally-obese people may develop
some of the symptoms of anorexia, in particular hyperactivity paired with lower thermogenesis, and potentially amenorrhea in women.
Aside from leptin, the TRH portion of the hypothalamus appears to be most sensitive to T
3. Many tissues have the ability to convert T
3 to T
4, but the hypothalamus isn't one of them. It is reliant on other tissues to produce T
3.
Lechan and Fekete (2004) state that,
The source of nuclear T3 responsible for feedback regulation of TRH neurons in the PVN (RM: paraventricular nucleus, a component of the hypothalamus) differs from the source of T3 in other regions of the central nervous system (CNS) such as the cerebral cortex and anterior pituitary, where the majority of T3 arises from the intracellular monodeiodination of T4 to T3 by type II iodothyronine 5'-monodeiodinase (D2) (62). This is because the PVN contains little, if any, D2 activity or D2 mRNA (63, 64).
The key take home point is that free T
3 in the bloodstream regulates TSH production (with at least one major exception), while many other parts of the body (e.g. skeletal muscle) which have an active deiodinase system may be more sensitive to T
4, which exists at much higher concentrations. I will discuss this further later on.
The Lechan group has followed up there results with an effort to see if inflammation can affect the TRH neurons directly (
Sanchez, 2008). Cortisol may be considered the whole-body response to inflammation, and the Sanchez group did not find that it seriously impacted the TRH neuronal activity. They did, however, find that local inflammatory paracrine hormones (i.e. cytokines, which I like to refer to as immune system catnip) could turn on D2 genes found in specialized neuron supporting cells known as tanycytes (and they were hardly the first group to notice this association). Specifically, when they injected rats with bacterial lipopolysaccharide, the D2 activity in the tanycytes was turned on, and since these glial cells are adjacent neighbours to the TRH neurons we would expect the local T
3 concentration in the TRH neurons to be higher. This in turn is going to down-regulate TSH production by the pituitary gland, as well as the other hormones the TRH neurons innervate (prolactin, oxytocin, and arginine vasopressin).
Lipopolysaccharide is a big word, so to simplify things just note that it is a component of bacterial cell walls, which are considerably different in composition from our cell membranes. Lipopolysaccharide is considered an
endotoxin, and the two words are essentially synonyms as far as immunology is concerned. The innate immune system (neutrophils, macrophages, and natural-killer cells) can recognize it as hostile, and attacks. In general, I would expect the whole body to respond to an infection via a fever, so at first glance this feedback mechanism seems to be going the wrong way! However, we have to consider the evolutionary notion that all human cells might respond the same way, since bacteria don’t use thyroid-hormone as a DNA transcription activator. A bacterial infection
in close proximity to the hypothalamus could result in down-regulation of TSH and hence T
4 levels. If an infection lasts a long time, then overall T
4 levels may be depleted over time and become depressed compared to normal.
This is especially so because the rest of the body's D2 will also increase T4 to T3 conversion as a result of inflammatory signals triggered by the infection, thus depleting the T4 reservoir in the blood stream while simultaneously the thyroid is signaled to produce less T4.
Chronic (aka latent) infections are quite possible, especially from organisms that are good at mimicking the host’s biochemistry and avoid total destruction at the hands of adapted immune system. In particular the Herpes family of viruses is well known for causing latent infections (e.g. see
Grubor-Bauk, 2008 for where I am going with this), and I have previously made the case for chronic/latent bacterial infection causing atherosclerosis. Viruses have not yet been shown to cause the same effect, but they still cause a local inflammatory response. Sachez notes that, “Other mechanisms, such as an increase in proinflammatory cytokines, may be of primary importance in the D2 response to LPS,” so I feel reasonably safe in generalizing this phenomenon to viruses as well.
Interestingly there doesn’t appear to be a specific known system whereby the adapted immune system can recognize the hypothalamus as non-self tissue and attack, i.e. there is no known form of autoimmune hypo-hypothamalitis (it doesn’t exactly roll off the tongue now does it). Neurons are not supposed to be affected by the adapted immune system (T-cells and B cells), so the dogma says neurons should not suffer from autoimmune diseases. This is because neurons lack certain surface proteins, namely from the major histocompatibility complex (MHC). However, natural killer (NK) cells, which are part of the innate immune system but are really a variant of T cells, express different types of surface proteins, such as the KIR class (
Cooley, 2006), and they are known to attack neurons and their accompanying cells (
Hickey, 1992 and
Darlington, 2008). If I can leave you all hanging for a couple months, I am pretty sure at this point that chronic fatigue and immune dysfunction syndrome/ myalgic encephalomyelitis/ fibromyalgia is precisely this pathology and is inducted largely by Epstein-Barr or cytomegalovirus infections that become latent in the hypothalamus.
Overall the endotoxin/LPS-induced dysfunction of the hypothalamus hypothesis seems to be strongest fit to hormone status for the actual case of acute non-thyroidal illness (
de Groot, 2006) so I feel that this is probably one of the strongest potential pathologies for a chronic form of the same.
The Pituitary Gland
The pituitary is located directly underneath the hypothalamus but outside the blood-brain barrier, which enables it to discharge large quantities of peptide hormones into the bloodstream. Although the cell bodies of the TRH neurons are located in the hypothalamus, their axons (which is the long structure that action potentials are fired down) actually snake from the hypothalamus down into the pituitary, where they terminate. The separation between the TRH neurons and the thyrotropin (TSH) producing cells of the pituitary gland serves a couple of functions. One, the signal produces by the TRH neurons can be greatly amplified by having each of them stimulate many specialized endocrine cells. Second, the pituitary is outside the blood-brain barrier, which facilitates dumping relatively large peptide hormones into the blood. Incidentally, many of the hypothalamic neurons that penetrate into the posterior pituitary are essentially by-passing the blood-brain barrier. There are also channels from hypothalamus into the anterior pituitary, which is where all the major pituitary hormones are produced.
The pituitary itself can suffer from degenerative disease such as lymphocytic hypophysitis, which is an autoimmune condition of the pituitary gland (
Rivera, 2006 and Crock et al. (
Autoimmune Hypophysitis in “Autoimmune Disease in Endocrinology,” ed: A.P. Weetman, Humana Press, Totowa New
Jersey (2008)). It also goes by other names, such as autoimmune hypopituatarism. There is also an atrophic form where the pituitary is shrunken and scarred by the autoimmune assault, known as granulomatous hypophysitis. When the pituitary is damaged typically more than one hormone is affected especially as the disease progresses. Adrenocorticotropin (ACTH) deficiency is the most common (60-60 %), followed by thyrotropin (TSH) deficiency (47 %), gonadotroponin (FSH/Lutein) deficiency (42 %), and growth hormone deficiency (42 %). Prolactin deficiency also manifests (34 %), possibly in conjunction with TSH deficiency. Headache is often associated with it, although that is a very non-specific symptom. Approximately 0.5 % of the population appears to be afflicted and I have to say, the quantity of research on this subject is seriously deficient considering just how many people must be affected. Autoimmune hypopitutarism is strongly associated with autoimmune thyroiditis, with perhaps 40 % of Hashimoto’s patients also having some degree of hypopituitarism.
I have used Table 1 before, and I present it again because it’s the best way I have to present the many functions of the pituitary gland without a massive wall of text. In general, when the pituitary isn’t functioning correctly, a huge variety of symptoms can present themselves.
Table 1: The hypothalamic/pituitary axis hormones and their actions on the human body.
Hypothalamus/Pituitary hormones | Description |
Corticotropin-Releasing hormone (CRH) / Adrenocorticotropic hormone (ACTH) | Stimulates the adrenal glands to produce cortisol, a very important general stress hormone that among other things regulates activity of the immune system. |
Growth-hormone Releasing Hormone (GHRH) / Growth-Hormone (GH) | Turns on fat metabolism and turns off protein and carbohydrate metabolism, putting the body in a fasted state. Circumstantially may stimulate production of insulin-like growth factor (IGF1) which is responsible for much protein synthesis in bone, skeletal muscle, and many other tissues. |
Thyrotropin-Releasing Hormone (TRH) / Thyrotropin (TSH) | Stimulates the thyroid gland to produce T4, the inactive basal metabolism hormone. T3, the active form, is produced by seleno-deiodinases (D1, D2) found in many tissues but in humans predominately the liver and skeletal muscle. T3 is required for the transcription of all proteins (via messenger RNA) from DNA. |
Gonadotropin-Releasing Hormone (GnRH) / Follicle-Stimulating Hormone (FSH) | Stimulates the gonads to mature germ cells (eggs and sperm) |
Oxytocin (OT) / none | Neuropeptide that down-regulates activity of the amygdala, the anxiety-centre of the brain. Thought to have an important role in social cognition and mood, possibly responsible for “motherly” stereotypical behaviors. Also responsible for uterine contractions during childbirth and menstrual cramps. Can cause spontaneous miscarriage by this mechanism. |
Arginine Vasopressin (AVP) / none | Triggers pair-bonding, jealousy, and other ‘male’ stereotypical behaviors. Also acts on the kidney to regulate water retention |
Dopamine & TRH / Prolactin Hormone | Dopamine is the Prolactin inhibiting hormone while Thyrotropin-releasing hormone serves a dual role as the stimulating hormone. Prolactin is nominally responsible for lactation during breast feeding but perhaps more interesting is responsible for sexual satisfaction and orgasm in both men and women. |
Gonadotropin-Releasing Hormone (GnRH) / Luteinizing Hormone | Triggers ovulation in females, with associated drop in estrogen and rise in progesterone. Triggers release of testosterone in males. |
The headache and mass-effect symptoms (i.e. impaired vision) of hypophysitis may be associated with nausea, fatigue, and anorexia (lack of appetite). Hypophysitis often manifests after childbirth in the post-partum period, and in this case excessive production of prolactin (and hence breast milk) can occur analogous to Grave’s disease (hyperthyroidism). Lastly, diabetes insipidous is associated with hypophysitis, although lymphocyctic hypophysitis is usually considered to be a disease of the anterior pituitary gland. Diabetes insipidous occurs in the posterior pituitary, and involves dysfunction of arginine vasopressin, otherwise known as anti-diuretic hormone (ADH).
Diagnosis of hypopituitarism is challenging. Due to its location in the middle of the skull and small size, the pituitary is dangerous to biopsy. MRI can sometimes show an enlarged or shrunken pituitary gland. Low circulating levels of any of the pituitary hormones can indicate hypophysitis but they can also signal other problems with feedback in the hypothalamus or pathology of the hypothalamus proper. There is an anti-pituitary antibody test for lymphocytic hypophysitis but it is not very specific, likely due to the presence of five major forms of endocrine-hormone releasing tissue in the pituitary. One of the first groups to survey anti-pituitary antibodies (
Stromberg, 1998) only found it in 28 % of their hypophysitis patients although test practices seems to have improved substantially since then by my reading of the literature. The link to celiac disease (below) seems to associate anti-pituitary antibodies with growth hormone deficiency in particular.
A hallmark of lymphocytic hypophysitis is atrophy of the gonads, adrenals, and thyroid gland. Endocrine tissue is much like muscle in that you either use it or lose it. If the pituitary isn’t stimulating these organs, they’ll shrink under the lesser workload, similar to how men who take synthetic testosterone have shrunken testes. This brings up an aside, that it’s difficult once a patient gets onto hormone-replacement therapy to get them back off, even if the autoimmune reaction is no-longer ongoing.
One of the more interesting associations of lymphocytic hypophysitis appears to be with celiac disease. If you are familiar with gluten sensitivity, you are probably aware that there are some idiopathic forms (i.e. those without known pathologies). An Italian group found that some 40 % of newly diagnosed celiac patients had anti-pituitary antibodies in their blood serum and it resulted in at minimum growth hormone deficiency (
Delvecchio, 2010 and
my post on the subject).
Thyroid Gland
Because one can find decent descriptions of hypothyroidism on the internet, I’ll not spend a great deal of time on this section, especially since I am interested in conditions where the thyroid works properly but basal metabolism is still depressed. The thyroid is a gland located on the throat that, under stimulation by TSH produces Thyroxine (T
4) from tyrosine amino acid residues. It also needs iodine, namely four atoms per hormone molecule (which is where the four-subscript comes from). The fabrication of T
4 is affected by two enzymes, thyroid peroxidase (TPO) and thyroglobulin (Tg).
There are two forms of autoimmune thyroiditis: Hashimoto’s, which is lymphocytic, meaning that the thyroid is so packed with immune system cells that it swells and presents as a goiter; and Ord’s, which is the chronic fibrosis form with an atrophied and scarred thyroid gland. Functionally Ord’s and Hashimoto’s appear to have similar outcomes, but present different symptoms. TPO antibodies typically indicate the goitergenic form while Tg antibodies alone indicate the atrophic form. TPO antibodies are considerably more common in Hashimoto’s thyroiditis than thyroglobulin antibodies. That unfortunately means Tg-antibodies often aren’t often tested for. Patients should be aware of this potential for false negative test results in autoimmune hypothyroidism, especially in conjunction with no goiter. If T4 is low and TSH is high, make sure to get the Tg-antibody test if the TPO test comes back negative.
With the requirement of iodine, an element that can be in short supply in the diet, many people advocate supplementing with iodine especially if it isn’t taken in the form of iodized salt. However, I would be remiss if I didn’t mention that there is a strong body of research out there that shows that removing iodine from the diet can arrest hypothyroidism so I would caution people against taking large doses of iodine without being aware of the potential for an adverse outcome (
Kasagi, 2003 and
Yoon, 2003).
A number of dietary factors can also cause goiter and subclinical hypothyroidism. The main offender that I see mentioned in the literature is soybean protein products. The offending isoflavone found in products containing soy protein is called genistein (and to a lesser extent the isoflavone daidzein).
Doerge and Chang (2000) found that genistein irreversibly bound to TPO and stopped its action permanently (in rats). They did not, however, find that T
4 levels were actually affected. Rather the production of TSH increased to induce the thyroid to build more TPO. Similarly another rat study found that the deiondinase system which converts T
4 to T
3 also increased its activity to compensate (
Simmen, 2009, please note that no direct effect of genistein on hepatic gene regulation was demonstrated). Thus I conclude that reasonable quantities of goitrogens are safe for people with healthy basal metabolisms. On the other hand, if you are hypothyroid, why add additional stress on the system? This goitrogenic effect could still cause problems in a low-iodine environment, however, as iodine consumption also increased.
My main concern in this case is that soy (and other goitrogens) might actually induce autoimmune disease. If genistein binds irreversibly to TPO, it will change the shape/conformation of the TPO somewhat. If you are unlucky, a receptor on an immune B cell may then recognize the misshapen TPO as a foreign body and launch an autoimmune attack on the thyroid gland. This is the ‘superantigen’ hypothesis from autoimmunity theory. The positive news to take from this hypothesis, if you remove the goitrogen, then the autoimmunity should also go away (given half a year or more for the gland to start to heal assuming it hasn’t been completely obliterated by the immune system).
Aside from soy, some of the other goitrogens that I see in the literature include corn, the African staple crops cassava and millet, cruciferous vegetables (cabbage, broccoli, brussel sprouts, etc.), strawberries, and peanuts.
Roman (2007) provides an exhaustive list of potential anti-thyroid agents (including pesticides and other environmental toxins) if the reader is inclined to investigate further.
Selenium Deiodinase Enzymes
Thyroxine (T4) as produced by the thyroid is not a very effective in up-regulating DNA transcription. In order for it to be truly effective, one of the four iodine atoms attached to it must be removed, turning it into triiodothyronine (T3). There are actually two forms of T3, depending on which side of the thyroxine molecule the iodine is removed from, and only one of which is biologically active. The chemically active form has the iodine removed from the left-hand side, while the right-handed form is inactive, and is usually annotated rT3 (standing for reverse T3). The removal of a second iodine results in T2, which is totally inactive.
Removal of iodine atoms is called deiodination, and it is accomplished by a set of globular protein enzymes know as the deiodinase family (
Bianco, 2003 provides a detailed if technical review). The deiodinases feature an active site with a selenium atom, which acts to catalytically cleave off iodine atoms from the thyroxine hormone. Selenium is an essential element required for deiodinase fabrication. There are three known deiondinase enzymes, type 1 and type 2 (abbreviated D1 and D2) both convert T
4 to T
3 and can also deiodinate rT
3, so they cooperate as the on-switches Type 3 deiondinase (D3) deactivates T
4 to rT
3 and both types of T
3 to T
2, so it acts as the off-switch.
D1 is found predominately in the liver and thyroid, as well as the kidney and pituitary gland and may be present in smaller quantities in other tissues. It is responsible for most of the circulating T3, since the thyroid and liver are the primary exporters of thyroid hormone to the body. About 10 % of the T4 produced by the thyroid is deiodinated before being released into the blood. D1 is a simplier complex compared to its cousin D2, and it is capable of producing either T3 or the inactive form, rT3, producing roughly equal quantities of both. The liver is also awesomely good at extracting thyroxine from the bloodstream, a point I will refer to in the thyroid transportation and storage section. D1 can produce T3 much faster than D2 can (i.e. it has a high reaction velocity) but it requires a much higher concentration of T4 which is probably why it is found predominately in the thyroid and liver.
D2 is predominately found in skeletal muscle, the heart, the brain and other nervous tissue as well as brown adipose tissue. D2 is apparently found in human thyroid tissue but not rat thyroids. It seems to have no proclivity to produce the inactive form rT3, but like D1 it can inactivate rT3 to T2. D2 is capable of functioning at much (~1000x) lower concentrations of T4 than D1 is (i.e. it has a high affinity for T4). Otherwise it is similar in function to D1.
D3 historically was thought to be largely present only during childhood but there is plenty of research now that suggests that is not the case and that it is heavily expressed in the brain and skin (
Kestler, 2006). After all, something has to inactivate T
3 to T
2, a point that some of the review articles I’ve read on the subject seem to have missed. Other research has pointed to activated immune system cells as potential sources for D3 activity (
Boelen, 2008 and
Boelen, 2009), which again points a potential finger at chronic infection/inflammation as a possible source of idiopathic hypothyroidism. One study published in the New England Journal of Medicine found that infantile
hemangioma’s could grossly over-express D3 production, resulting in severe hypothyroidism (
Huang, 2000). It’s also well known that placenta tissue expresses D3 heavily to protect the developing infant from the adult’s thyroid hormone levels, which could possibly account for post-partum hypothyroidism, but that is speculation on my part.
The D2 story is probably the most important from the point of view of a euthyroid sick syndrome. This is because
local T3 concentrations in major tissues are determined by the local gene expression of the deiodinases, and not by blood T3 levels (
Kohrle, 2000). This is the reason for the heavy emphasis on circulating T
4 in testing for thyroid disorders. Thus the two principle requirements for maintaining a normal body temperature are:
- Sufficiently high concentration of circulating T4 in the blood.
- Proper gene expression of the deiodinases.
Circulating T3 is a proxy for D1 activity but not so much for D2 activity. It does interact with the hypothalamus as a feedback signal, but the majority of thermogenetic (heat producing) activity in the body is going to occur in the big energy-intensive tissues of striated muscle (including heart) (D2), brain (D2), and liver (D1). If a person has normal T4 but a low basal temperature, the problem isn’t the thyroid.
The similar overlapping functions of D1 and D2 begs the question, what is the evolutionary significance of having two enzymes for the same function? As I’ve mentioned above, D2 seems to express in tissues that are required in survival situations: nervous and muscular tissue primarily. In comparison, D1 appears in tissues used for digestion (and presumably reproduction). On such a basis I would hypothesize that high stress will up-regulate D2 expression and down-regulate D1 expression.
Gene expression of the deiondinases is modified by a whole suite of hormones. Unfortunately, most of the data on this subject comes from rodents who have substantial differences in their deiodinase system compared to humans. For example, rodents do not produce D2 in their skeletal muscle, but humans do. I suspect much of the contradictory results in the research surrounding the selenium deiodinase activity are due to interspecies variation, and variation amongst rodent lines. Nonetheless, I present the data for rodents in Table 2, but please be aware it may be flat-out wrong.
Table 2: General effects of endocrine hormones on D1 and D2 activity in humans (from Bianco and Kohrle)
Hormone | Effect on D1 activity | Effect on D2 activity |
Androgens (testosterone) | Increases (tissue specific – liver) | Unknown |
Estrogens (estradiol) | Increases (tissue specific | Unknown |
Glucocortoroids (cortisol) | Decreases | Trivial increase |
Catecholamines (adrenalines) | Unknown | Increases |
Growth hormone (GH) & Insulin-like growth factor (IGF-1) | Increases ratio of T3 to T4 and reduces rT3; could also be down-regulating D3 | Unknown, likely similar to D1 |
Thyrotropin (TSH) | Up-regulates thyroid D1 indirectly | Increases |
Cytokines (i.e. ‘inflammation’) | Decreases | Increases |
Insulin | Increases | Increases |
Glucagon | Decreases | Unknown |
Cold exposure | Increases | Increases |
Reverse T
3 is an interesting molecule that could potentially cause a lot of problems if the balance of T
3 to rT
3 was overly altered. It acts as a highly competitive inhibitor for the T
3 in DNA transcription, which means it gets into T
3 spot but it doesn’t cause the correct shape changes that allows DNA to be copied into RNA. It’s likely very difficult to tell rT
3 from T
3 in the lab since they have the same molecular weight and very similar chemistry (e.g.
Zhang, 2005), such that your average commercial lab cannot tell the difference. Both D1 and D2 do remove rT
3 by transforming it to T
2 so it is not clear at all whether rT
3 can cause physiological problems. When considering D1 alone there should be some steady state quantity of rT
3 in tissues that are served by thyroid and liver-derived T
3. I personally suspect rT
3 is involved in the local regulation of T
3, in that it prevents local tissues that produce T
3 for export to the body from overwhelming their oxygen and nutrient supplies.
I did find one mention for potential pathology for rT
3 from
wikipedia:
rT3, unlike T3, does not stimulate thyroid hormone receptors. However, rT3 nonetheless binds to these receptors, thereby blocking the action of T3. Under stress conditions, the adrenal glands produce excess amounts of cortisol. Cortisol inhibits the conversion of T4 to T3, thus shunting T4 conversion from T3 towards rT3. Consequently, there is a widespread shutdown in T3 binding across the body. This condition is termed Reverse T3 Dominance. It results in reduced body temperature, which slows the action of many enzymes, leading to a clinical syndrome, Multiple Enzyme Dysfunction, which produces the effects seen in hypothyroidism. Effects include fatigue, headache, migraine, PMS, irritability, fluid retention, anxiety and panic.
The only scientific literature I was able to find on this subject was in the Puerto Rico health sciences journal, which seems a strange place for a doctor from Vermont to publish (
Friedman, 2006). Personally, I am inclined to treat Wilson’s thyroid syndrome as a wikipedism for now as I am unclear on how cortisol could directly affect the conversion of T
4 to rT
3 unless it is capable of directly binding to D1 in an allosteric fashion.
One potential link to autoimmunity has been the discovery of anti-D2 peptide antibodies and the fact that they are commonly found in association with anti-pituitary antibodies (
Nakahara, 2005). They found 32 % of their Hashimoto’s patients had anti-pituitary antibodies and 27 % had anti-D2 peptide antibodies, with only a weak correlation between the two (R
2 = 0.33). The researchers apparently thought that D2 could be the antigen for the anti-pituitary antibody but their results didn’t support their hypothesis very well. This underscores a point that I would like to make: Hashimoto’s thyroiditis may have consequences that extend outside of the thyroid in a large minority of patients, so if T
4 replacement therapy doesn’t provide relief for symptoms, then there may be problems upstream or downstream of the thyroid gland. Autoimmune diseases have a tendency to cluster.
From my reading of many of the articles relating to the deiodinases it does seem clear that fasting will decrease thermogenesis (
Coppola, 2005) and in particular serum T
3 decreases, but should only do so in a transitory fashion. I plan to return to this topic at a later date, since it requires a more in-depth discussion than I want to provide in this review. The implication from my point of view is that while circulating T
3 drops during fasting, the brain, heart, and skeletal muscle, which all rely on D2, will be less affected and this seems to lead to hyperactivity, so the net effect on caloric expenditure may be minor. For most people, fasting remains a good was to restore heath to a damaged liver but if you have low T
3 blood levels avoid fasting as a weight-loss technique.
Transport and Storage of Thyroid Hormones in the Blood
This last section is largely regarding the role of the liver in basal metabolism. Many diseases of the liver are associated with poor thyroid function (
Malik, 2002), including cirrhosis. Malik’s article also makes the point that α-interferon, sometimes used as an antiviral drug, can induce autoimmune diseases including hypothyroidism. In addition to producing more serum T
3 than any other organ, including the thyroid, the liver is also responsible for fabricating all the proteins that transport thyroid hormone in the blood.
Many hormones in the blood that are not water soluble (especially steroids and thyroid hormones, which are lipids) are often bound to transport proteins, specifically
thyroxine-binding globulin (TBG), albumin, and
transthyretin (aka prealbumin). Through random chance, some hormones dissociate and some bind such that equilibrium is formed between bound and unbound hormone. Typically only 0.02 % of T
4 and 0.3 % of T
3 in the blood is actually unbound. Typically 75-80 % is bound to TBG, 15-20 % to transthyretin, and 5-10 % to albumin.
The
free hormone hypothesis states that only the unbound (or free) concentrations of thyroid hormones are important to determine concentration inside the cells of body tissues. However, the three transporting hormones have differing properties and the free hormone hypothesis misses some key points. First, the binding half-lives for albumin and transthyretin are considerably shorter than TBG, so when in the capillary bed, as the free hormone is taken up by tissues that which is bound to albumin and transthyretin will tend to dissociate to restore the equilibrium (Fig. 1). This acts to keep the concentration of free thyroid hormone constant as the blood passes through the capillary bed, so that tissues more on the venous side of the circulatory system are not thyroid-hormone deprived. In this case, the amount of
bound thyroid hormone also matters. This is known as the
free hormone transport hypothesis and is almost exclusively the brainchild of
Mendel, 1992. Depending on the length of the capillary bed that feeds them, different tissues may be more or less sensitive to either unbound or bound thyroid-hormone concentrations.
Figure 1: (A) Dissociation rate of T4 from transthyretin and, (B) from thyroxine-binding globulin (TBG) (from Mendel, 1988). Typically it takes 60 seconds for blood to circulate.
The liver actually uptakes an amazing amount of the total T4 in the blood, about 10-12 % per pass. Note this is not 10 - 12 % of the free T4, but 10-12 % of all T4 including bound T4 that passes through the portal vein, which in turn is about 20 % of the blood supply. That means literally the liver is up-taking about two-hundred times the total available free T4, every time the blood circulates past. It doesn’t take a genius to realize that this means that free thyroid hormone levels are not the be all and end all. As you might expect from this result, the liver has the ability to pick-up thyroid hormone in the bound form (i.e. attached to serum proteins) directly from the blood.
Where Mendel was going with his line of thinking appears to have been that an upset in the balance of binding affinities (i.e. too much TBG compared to transthyretin) could reduce the rate at which T
4 diffuses into the tissues and hence be a potential cause of non-thyroidal illness (
Mendel, 1991). Alternatively other serum molecules in sick patients could bind to the thyroid-binding proteins (either at the binding site or somewhere else), radically changing their affinity to thyroid-hormone such that they hold onto it far too tightly or not at all. Overall, Mendel’s results were negative for a binding inhibitor but some other research has suggested that free-fatty acids (FFA) as a possible culprit (
Chopra, 1986). Recall that free-fatty acids are often a product of a fatty liver overburdened with fructose intake. Other research found that
bilirubin could act to inhibit uptake of T
4 into the liver (
Lim, 1993). Research in this area seems to have petered out over the last decade; if there are effects, they may be indirect and not causative.
Conclusion
Overall, there is a fair amount of evidence to suggest that autoimmune hypothyroditis may have additional complications beyond the thyroid-gland itself, or that chronic conditions may be resulting in poor basal metabolism even with euthyroid status. This seems particularly evident for potential problems upstream of the thyroid, in the hypothalamic/pituitary axis. The deiondinase system is also very likely to be a source of problems, particularly with regard to the many factors that regulate it. The main trouble with diagnosing problems with the deiodinase system is that it is very complicated and much of the data are contradictory. This area will continue to develop and perhaps over the next five years the picture will be much clearer than it is now.
This review is not even close to exhaustive; that would require a book. For those of you with unresolved basal metabolism problems I hope I have provided you with some food for thought to try and resolve them. On the other hand, if you are a hypochondriac you probably should have stopped reading at the title. Sorry.
