This chapter is related to Section U1(v) from the 2017 CICM Primary Syllabus, which asks the exam candidate to "describe the control, secretions and functions of the thyroid". For reasons of convenience, it also includes some Section U2(iv), "understand the pharmacology of thyroid hormones", even though that has never been included in exam questions. Past papers have only included the following:
The exam candidate may be dismayed to learn that the CICM Second Part Exam has a lot more thyroid content, for which the First Part exam material may not be a logical antecedent. This material includes:
For that reason, i.e. to increase the connection between the two stages of CICM training, this chapter includes some material which might appear peripheral or excessive to the task of answering the paltry handful of First Part questions.
That material, in summary:
- Structure of the thyroid
- Large (10-20g) endocrine gland, two symmetrical lobes anterior to the 2-4th rings of the trachea, with rich blood supply
- Organised into follicles: colloid-containing cavities lined with cuboidal epithelium
- Colloid is made up of iodinated thyroglobulin, the precursor for thyroid hormone synthesis
- Synthesis of thyroid hormones
- Iodine is absorbed from diet as iodide and concentrated by 30-40 times in the thyroid follicles by the sodium/iodide symporter (NIS)
- Thyroglobulin is then iodinated by the actions of thyroid peroxidase
- Iodinated thyroglobulin is stored, and reabsorbed as needed by follicular cells
- Proteolysis of thyroglobulin liberates T3 and T4 molecules
- Circulation of thyroid hormones
- Released thyroid hormones consist of 80% T4 and 20% T3
- Circulating T4 and T3 are highly protein bound to thyroid hormone-binding globulin, a chaperone protein in the plasma
- T4 has a longer half life (6-7 days), gradually converted to T3 by peripheral deiodinase enzymes (ubiquitous, but mainly in the liver and kidneys)
- T3 has a shorter half life (hours) and is the main biologically active thyroid hormone
- Actions of thyroid hormones
- Bind to mainly nuclear receptors, which act as transcription factors, modifying protein synthesis (though there are also cytosolic and membrane receptors)
- Most physiologically important actions are mediated by gene transcription and therefore take more than 24hrs to manifest
- Actions of thyroid hormones include:
- Increased cardiac output due to increased contractility, and decreased peripheral vascular resistance)
- Increased sympathetic nervous system activity, increased sensitivity to catecholamines
- Psychological and neurodevelopmental effects
- Increased renal blood flow and increased clearance rate of renally cleared substances
- Increased hepatic protein synthesis and increased hepatic blood flow, with increased clearance rate of substances metabolised by the liver
- Increased gastrointestinal motility and increased appetite
- Increased blood flow to skeletal muscle
- Increased shivering and nonshivering thermogenesis
- Increased total body metabolic rate and oxygen consumption:
- Increased gluconeogenesis increased hepatic glucose output
- Decreased efficiency of mitochondrial electron transport, resulting in heat production
- Increased lipolysis in white adipose tissue, ncreased free fatty acid release, increased hepatic lipogenesis, and increased use of lipids as metabolic fuel substrate
- Reverse cholesterol transport
- Regulation of thyroid hormones
- Release of TRH is stimulated by low T4/T3 levels and cold temperature
- TRH stimulates TSH release (which is inhibited by high T4/T3 levels, as well as somatostatin, dopamine and cortisol)
- TSH stimulates T3 and T4 release
- Conversion of T4 into T3 is also controlled by regulation of peripheral deiodinase activity
Stathatos (2012) or Stathatos (2019) are the most suitable references for rapid revision mainly because both are brief and devoid of unnecessary fluff. On the other hand, the reader unburdened by time constraints can be directed to the Endotext entry by Maenhaut et al (2015), and to the 40-page review of thyroid hormone synthesis by Carvalho & Dupuy (2017) Most of the information gathered here comes from the latter, as well as excellent works by Hisao Fujita (1975 and 1984)
The intensivist rarely needs to contemplate the anatomy of the thyroid gland, with the exception of the rare scenario where a goitre may act as an airway obstruction, or in the less rare scenario where the intensivist has accidentally pierced it in the course of performing a percutaneous tracheostomy.
Anatomy of the Thyroid Gland
- Landmarks: The thyroid spans the C5-T1 vertebrae
- Basic structural anatomy: Two symmetrical lobes joined by an isthmus, in total weighing 10-20g
- Posteriorly, to the 2-4th rings of the trachea, and medial carotid sheat
- Anteriorly, skin, pretracheal fascia, sternothyroid and sternohyoid muscles
- Superiorly, the cricoid cartilage
- Medially, the larynx trachea and oesophagus, as well as the recurrent laryngeal nerve
- Blood supply:
- Superior thyroid artery
- Inferior thyroid artery
- Thyroidea ima artery (in about 3% of people)
- Venous drainage:
- Into the superior, middle and inferior thyroid veins
- Sympathetic supply from the middle cervical ganglion
- Parasympathetic suppoly from the vagus
- Hormonal regulation of metabolic energy use primarily, as well as protein synthesis and cell division
The thyroid, if you think about it, is actually the largest of the endocrine glands. The pancreas may seem bigger but the vast majority of it is involved in exocrine function, making the adrenals the next largest competitor. Like most of the endocrine systems, this one is ancient, in the sense that basically anything with a neck has a thyroid gland (though to be fair it is not always in the neck). For example, tadpoles only differentiate into frogs under the influence of thyroid hormones, and hypothyroidism accounts for the perpetual tadpole state of the axolotl. Even echinoderms and molluscs seem to produce T4 and T3. There are more interesting details there, but the casual reader will likely revolt against any further digression in this direction, unless they are already given to leafing through Frontiers in Endocrinology at their leisure.
Each gland is an aggregation of smaller functional units, the thyroid follicles. Unlike virtually every other endocrine gland in the body, the thyroid cells do not store their hormone in some kind of concentrated intracellular granule - instead they prefer to surround a huge blob of precursor molecules, forming a sort of cyst. These cysts are the thyroid follicles, and the specially modified epithelial cells forming the walls are thyrocytes, or thyroid follicular cells. Occasionally one might hear them referred to as acini, but this is not standard nomenclature, and unlike other acini (eg. pulmonary or pancreatic) these ones do not communicate with anything, i.e. there are no ducts connecting them. Here, a gorgeous haemotoxylin-stained section of a rat thyroid gland from Mense and Boorman (2018) is left to break up the monotony of black and white text:
Speaking at least for the rat, we can say that each lobe contains about 300 such follicles. Each follicle is about 300 µm in diameter, containing a gelatinous glorp often referred to as colloid. This material usually looks pretty homogeneous on microscope sections, consists mainly of thyroglobulin, and is occasionally described as "sticky", suggesting that somebody has had the direct experience of feeling it with their bare hands.
This colloidal glug is certainly thick enough that diffusion of ions and thyroglobulin though it is probably one of the rate-limiting steps of thyroid hormone synthesis. According to micropuncture studies by Hayden et al (1970), the protein concentration here is about 260g/L, making colloid about three times thicker than blood plasma, with thyroglobulin the main protein ingredient (aside from the garnish of a little bit of mucopolysaccharide). This substance is slowly nibbled upon by the cuboidal epithelial cells that surround it, as they slowly erode at the edges of the thyroglobulin blob with the constant grinding of their apical cilia, giving rise to a pale "halo" of partially absorbed material around the circumference of each follicle. The effective absorptive surface of the follicle is further expanded by the presence of microvilli, which Fujita (1975) estimated to increase the inner surface area by a factor of three or four. Outside, thyroid follicles are wrapped in a capillary network clearly optimised to efficiently collect their secreted output, as captured in the excellent electron microscopy images by Fujita (1984):
Looking at those thick sausage vessels coursing through the upper right of this image, the reader may imagine that the thyroid gland probably enjoys a substantial blood flow, and they would be right. The normal perfusion of the thyroid is about 1.2 ml/g/min, or about 30ml/min for the average-sized euthyroid gland, which can more than double in cases of hyperthyroidism. Per gram, this makes thyroid blood flow twice as great as that of the brain, five times greater than the liver, and half as great as the blood flow of the kidneys. This wealth of perfusion has historically made thyroid surgery such a famously bloody affair that the French Academy of Medicine had to ban it in 1850, horrified by the violence. To quote Samuel David Gross (1886):
"If a surgeon should be so foolhardy as to undertake it. . . . .every step he takes will be environed with difficulty, every stroke of his knife will be followed by a torrent of blood and lucky it would be for him if his victim lives long enough to enable him to finish his horrid butchery. No honest and sensible surgeon would ever engage in it."
The manufacture of thyroid hormones requires a whole industrial apparatus, consisting of the following steps:
First you get the iodine. It is usually widely available in the Western diet, mainly by intentional or accidental iodination of ubiquitous foods such as bread and milk (eg. where potassium iodate is used as a bread conditioner). According to Rousset et al (2015), the daily intake is about 150-300 mcg, from a variety of sources.
Then you absorb the iodine. It is usually reduced to iodide (I-) in the gut, and is absorbed completely in the small intestine, becoming distributed into the extracellular fluid. From there (specifically from the plasma) the iodide is cleared by a combination of renal elimination and uptake into the thyroid, where the thyroid is responsible for the removal of about 12% of the total plasma iodide every hour. This extraction is mediated by the NIS transmembrane protein (Na-Iodide Symporter), which - as the name suggests - pumps iodide into the thyroid follicular cell by borrowing the awesome power of the transmembrane sodium concentration gradient. In this fashion, the iodide content of the cells increases massively, up to 30-40 times the plasma concentration. A large proportion of this actually comes from reclaimed iodide which happens to be liberated in the process of degrading thyroglobulin.
Then you iodinate the colloid. Iodide is fairly useless while remaining in the thyrocyte, and needs to be transported into the lumen of the police, where the thyroglobulin is. The follicular cells are clearly aware of this need, as free iodide only seems to last for about 20 minutes in their cytosol. The efflux of iodide through the apical plasma membrane is mediated by multiple proteins (pendrin, ClC5, anoctamin-1) the names of which are neither memorable nor important. The most essential concept to internalise here is that the thyroid gland, and specifically the content of thyroid follicles, is a concentrated reservoir of iodine in the body (70-80% of the total body iodine is contained in the thyroid)
Thyroglobulin is a huge cumbersome molecule, 670 kDa in mass, and therefore very awkward to manipulate (for the reader to make a reasonable comparison, probably the largest soluble protein enjoying routine traffic in the human body is the IgM pentamer, which weighs about 900 kDa). This huge molecule is a glycoprotein; about 10% of its mass is carbohydrate. It is synthesised in the follicular cell under the regulatory control of TSH, which stimulates adenylate cyclase and increases cAMP in the follicular cells. It is then ejected through exocytosis and added to the blob of stored thyroglobulin, where it slowly stews in iodine. Iodinated thyroglobulin is then cleaved into thyroid hormones, and these cleft (cloven?) hormones are reabsorbed back into follicular cells by endocytosis. Considering that under normal circumstances your thyroid gland is neither growing nor shrinking, one comes to the conclusion that this internal balance of endocytosis and exocytosis must be in some sort of steady-state equilibrium. Ericson (1981) describes the intricacies of this process in a lot more detail, all of which is entirely unnecessary for the CICM exam candidate.
This method of storing iodinated precursor proteins in the gland is an evolutionary reaction to the scarcity of iodine. The hominids fighting for survival in the Olduvai Gorge (or any inland vertebrates for that matter) would have had only unpredictable and intermittent access to dietary sources of iodine. At the same time iodine and thyroid hormones would have been necessary throughout their lifespan. Long-term iodine storage is therefore an evolutionary priority for any organism that insists on having thyroid hormone in a central role in their development and metabolism. Probably for this reason the structure and function of thyroglobulin is remarkably well preserved across all vertebrates, with all the important hormonogenic sections so homologous that the human follicular cells could probably switch to using a sea lamprey's thyrogobulin without any loss of function (Holzer et al, 2016).
Following from the above, thyroglobulin is just a pile of pointless glycoprotein unless it contains a high concentration of iodine. The molecule itself contains 66 tyrosine residues, of which about 30 can become iodinated. Adopting a biased halocentric worldview, it's not the tyrosines that get iodinated, it's the iodine that gets organified by being incorporated into tyrosine residues (Stathatos, 2012). This step takes place at the colloid-facing apical membrane of the follicular cells . As you can see from these selectively stained slices from Senou et al (2009) most of the iodination seems to happen at the periphery of the follicle, leaving the centre relatively free from the red-coloured immunodetection stain selective for of T4-rich thyroglobulin.
The enzyme responsible for the iodination of thyroglobulin is thyroid peroxidase, a selenoprotein which is inhibited by iodine (thus rendering it inactive in times of relative iodine repletion). Apart from the fact that it contains selenium, it is also memorable because it is usually the target for autoantibodies in Hashimoto's thyroiditis. The role of this enzyme is in oxidising the iodide ions, which is necessary for their incorporation into tyrosine residues. It is a transmembrane protein that sticks out from the apical surface of follicular cells, protruding into the lumen of the follicle where it can act on iodide and thyroglobulin. The iodide ions (I-) which it oxidises into iodine (I2) are then linked covalently to tyrosine, also under the influence of the same enzyme, producing several different iodinated iodo-tyrosine species, as follows:
The reader will note that the last steps of this iodination process are actual ready thyroid hormones. These form through the coupling of the other lesser iodotyrosine molecules. In order for this to happen, iodotyrosine donors and acceptors need to be arranged in the correct antiparallel position which would permit them to combine (Carvalho & Dupuy, 2017). Thyroglobulin is imperfectly structured to make this happen, and of the 25-30 tyrosine residues that can be iodinated by thyroid peroxidase, only up to 16 can be coupled to form something between two and eight molecules of finished T4 and T3.
The end result of thyroglobulin synthesis and iodination is the production of a storage form of thyroid hormones that can remain in the follicle for months and which is designed to buffer long periods of nutritional iodine deficiency. Thyroglobulin or thyroid hormone stores don't seem to be assessed directly by any author, but the iodine stores of the normal human appear to be 15-20mg, of which the majority (80%) resides in the thyroid, and considering that normal euthyroid iodine turnover is apparently something like 60-95 µg per day, theoretically that should give you something like 200-300 days of uninterrupted thyroid function.
In order to liberate thyroid hormones from these stores, one needs to break thyroglobulin into pieces. This happens both at the apical surface of follicular cells and inside their endosomes, and is mediated by various endopeptidases. Carvalho & Dupuy (2017) offer a most thorough breakdown of how this happens, and a detailed understanding of the process does not appear to be essential for the intensivist, except to conclude that at the end unequal amounts of T3 and T4 (20% and 80%) are produced and released from the thyroid gland. Of these, T3 is the biologically active form which brings to the thyroid hormone receptor, and T4 is a prohormone that must be deiodinated to form T3 in the peripheral tissues (though it does have some intrinsic biological activity itself, at humongous concentrations).
|Class||Thyroid prohormone||Thyroid hormone|
|Chemistry||Iodinated tyrosine derivative||Iodinated tyrosine derivative|
|Routes of administration||PO||IV (but could still be given orally)|
|Absorption||60%-80% oral bioavailability||97% oral bioavailability|
|Solubility||pKa=7.43; very slightly soluble in water||pKa=8.4; reluctantly soluble in water|
|Distribution||VOD = 0.15L/kg; highly protein-bound (to thyroxine-binding globulin)||VOD = 1.8L/kg; less protein-bound than T4 (30 times less affinity for thyroxine-binding globulin)|
|Target receptor||Not an active drug, but has some (low) affinity for thyroid hormone receptors, which are mainly nuclear receptors which act as transcription factors||Thyroid hormone receptors, mainly nuclear receptors which act as transcription factors, though some are transmembrane and some are cytosolic|
|Metabolism||Metabolised by deiodination, by tissue deiodinases - into T3 (which is active)||Metabolised by deiodination by tissue deiodinases, into various iodotyrosine species|
|Elimination||Inactive iodinated compounds undergo mainly hepatic metabolism. In overdose, some hepatic metabolism occurs, which results in enterohepatic recirculation|
|Time course of action||Half-life 6-8 days||Half-life 6-10 hours|
|Mechanism of action||Endocytosis by a variety of transmembrane transporters, and which binds to nuclear transcription factors to perform a variety of functions. Some actions are probably also performed by cytoplasmic and transmembrane receptors, which mediate more acute effects|
|Single best reference for further information||Colucci et al, 2013||X-gen pharmaceuticals PI document|
The pharmacodynamics section of the chapter on exogenous thyroid hormone replacement also explains the molecular effects of thyroid hormones, but we can revisit them briefly anyway. Briefly, for two main reasons: because no intervention is available to interfere with these steps directly, and because they are rather poorly understood. These factors make the intracellular exploits of thyroid hormones an unlikely target for the CICM examiners.
Still, for completeness, it it worth knowing something about these signalling pathways. Authoritative publications typically pull out a terrifying swarm of protein acronyms to describe them. Instead, the most simplified version possible would look something like this:
The thyroid hormone receptors are a diverse family of transcription factors that mainly sit in the cell nucleus and interact with the DNA, making them inaccessible from the cell surface. It was originally believed that the thyroid hormones penetrated the cell wall by passive diffusion, and then managed to make their way to the nucleus through the Brownian moshpit of the cytosol; but this is obviously preposterous because the distance is too great, and the concentration gradient is too small. It now appears that a whole host of transport proteins designed to move nonspecific organic anions could potentially act as a cooperative access point, admitting these hormones into the cell.
Thyroid hormone receptors are supposedly intranuclear and thyroid hormone effects are supposedly transcriptional and slow, but still there are some clinical effects (for example arterial vasodilation) that occur within minutes, which would be difficult to explain by gene transcription alone. It is thought that thyroid hormones also affect cytosolic protein function (for example, phosphoinositide 3-kinases), which bring about more immediate effects (for example, modifying the amount of intracellular calcium available to vascular smooth muscle). Henneman et al (2001) and Sinha & Yen (2018) are worthy references to explain these processes in much more detail than this author has the patience for.
By perusing the material below, the reader will eventually come to the conclusion that the heading here should probably say "physiological effects of the wrong amount of thyroid hormones", as it is easiest to characterise these effects by borrowing from our shared clinical experience of hyperthyroidism and hypothyroidism. The rationale for this approach is that it could make the subject matter easier to recall in an exam, notwithstanding the deep love we all feel for memorising lists. Unfortunately, thyroid hormones are another bunch that could be described as "pleiotropic", meaning that they have diverse effects on basically all body systems, which make this section long and poorly organised. The reader planning to read further is consoled with the promise that some legitimate peer-reviewed references are left as mileposts on their meandering journey.
Well, reader, of direct airway effects, they probably have none, though there are concerns that hypothyroidism could lead to the weakness of upper airway reflexes and promote sleep apnoea. That is a fairly remote concern for the intensivist, who has in their possession a whole range of non-invasive positive pressure devices with which to overcome this problem. Still, hyperthyroidism is known to cause a skeletal muscle myopathy which can affect both pharyngeal and oesophageal muscles, making intubation both more likely and more dangerous (as the risk of reflux and aspiration increases).
A more exciting indirect relationship is the possibility that the thyroid-deranged patient harbours a large unrecognised goitre, and that this goitre is waiting for the respiratory muscles to relax with rocuronium, so that it may collapse backwards upon the subglottic trachea and obliterate the middle airway during intubation. If this is happening, it would not be immediately obvious to the airway operator, and would manifest as either an impossible-to-advance endotracheal tube, or an impossibly difficult bag-valve-mask ventilation in spite of a clearly well-positioned tube. Judging by some large head-and-neck case series from major tertiary hospitals, it appears that being forewarned about this situation is protective (Dempsey et al, reporting in 2013, had surprisingly few airway complications).
Interestingly, the best most highly concentrated resource for the respiratory effects of thyroid hormones was this article from UpToDate, and there does not appear to be a satisfactory freegan alternative. For those who are not inclined to pay an annual fee, the basic points are outlined here:
Some baffling choices made by the author have relocated the detailed explanation of these effects to the chapter on the pharmacology of thyroid hormones (because that's presumably where the reader would first look when confronted with the need to infuse IV T3 as an inotrope). To summarise, thyroid hormones act as inodilators. Peripheral vascular resistance decreases (fairly acutely) and cardiac contractility increases (gradually, over 24 hours), with a resulting net increase in cardiac output. The only case series which demonstrated these effects was Malik et al (1999), whose patients' response to IV thyroxine looked gradual and levosimendan-like. One unique aspect however is the effect of thyroxine on the pulmonary circulation: there, it acts as a vasoconstrictor (upsetting the normal process of hypoxic pulmonary vasoconstriction), increasing RV afterload and potentially becoming a nuisance. The reader should not be seduced into thinking that this is Grade A evidence - our data on the pulmonary effects of thyroxine comes from disembodied rat lungs (Herget et al, 1987), as well as the observation that pulmonary hypertension often accompanies hyperthyroidism.
It would probably be best to separate the neurological effects of thyroid hormones into neurodevelopmental (covered in Prezios et al, 2018) and functional (discussed by Bernal, 2007). The latter are probably of greatest interest to the intensivist, mainly in the sense that severe hypothyroidism is one of the differentials in the diagnosis of an otherwise unexplained reduced level of consciousness. Thyroid hormone receptors are certainly found among all neurons and glial cells, and there is a clear relationship between thyroid function and neurological development, but nobody knows exactly how this works (except to point to various genomic effects). Similarly it is obvious that the thyroid hormones do something important to support normal cognitive function in the adult brain, as the effects of hypothyroidism and hyperthyroidism are both profound and broad (ranging from lethargy depression insomnia and anxiety to seizures and coma). Anderson (2001), looking at this, couldn't even pinpoint whether these effects were directly due to thyroid hormone receptor binding, or due to the secondary effects exerted through other systems.
Like with all things thyroid, there is an association between thyroid hormone derangement and electrolyte derangement, and "association" is as scientific as this gets. For example, Krishna et al (2018) were able to demonstrate a statistically significant trend towards hyponatremia, hypochloraemia and hypokalemia in hypothyroid patients. Defying logic, more thyroid hormone does not mean more sodium potassium or chloride (though they do seem to become hypokalemic occasionally). None of the authors writing about this association have produced specific evidence to implicate any specific physiological process which might be responsible for these changes, though hypothetical mechanisms include a hypothyroidism-induced decrease in the plasma renin and aldosterone activity, decreased Na+/K+ ATPase activity, and increased vasopressin release.
Reviewing the literature on the direct and indirect effects of thyroid disease on renal function, Mariani & Berns (2012) were able to identify the following:
Conversely, renal disease can have all kinds of effects on thyroid function, for example by decreasing the amount of thyroid-binding globulin available (via nephrotic syndrome), but this is probably something of a tangent.
Daher et al (2009) is the milepost reference for the gastrointestinal consequences of dysthyroidism, and is an excellent read, difficult to surpass in terms of clarity and structure. It is not possibly to simplify their contents as merely "lazy thyroid = lazy bowel", as for example diarrhoea and hypermobility could arise from either an excess or a deficiency of thyroid hormones. In short:
Thyroid hormones directly stimulate the synthesis of erythropoietin and promote the multiplication red cell precursor cells, supporting haematopoiesis. Ahmed & Mohammed (2020) determined that the usual consequence of hypothyroidism is a microcytic hypochromic anaemia. The converse is not true, i.e. hyperthyroid patients are usually not polycythaemic, suggesting that there is some sort of ceiling effect.
Again, though there is a well-established association between thyroid function and immune function (especially innate immunity), the mechanisms remain "complex and still not completely understood" according to Montesinos & Pellizas (2019) whose article seems to be literally the only review on the subject. Neutrophils monocytes and NK cells definitely seem to increase their activity in the presence of adequate thyroid hormone, and are relatively sluggish without it. It is unclear whether this results in any clinically relevant immune deficiency, nor is there any reason to believe that hyperthyroidism results in some kind of preternaturally enhanced immunity (or autoimmune disease).
Metabolic regulatory effects of thyroid hormones are mainly said to be mediated by receptors present in the liver, white and brown adipose tissue, and in skeletal muscle, though realistically all tissues metabolise something and those receptors are almost everywhere. Mullur et al (2014) goes into more detail here, but the main points are that thyroid hormones activate various intracellular signalling pathways and nuclear transcription systems which lead to:
The upshot of this for the intensivist is mainly reflected in the increased dietary requirements and the increased metabolic rate producing an increase in the total oxygen consumption. Hyperthyroidism is famously one of the differentials for explaining an increase in the oxygen extraction ratio (O2ER) which is not associated with a decreased oxygen delivery, i.e. it is a genuine increase in the DO2. It could be substantial - in a population of non-critically-ill hyperthyroid Swedes, Jansson et al (2001) found a 22% difference in oxygen consumption between pre and post-treatment states. Logically, hypothyroidism should result in decreased oxygen consumption, and this was also demonstrated experimentally by Sadek et al (2017).
"Central" and "key" were the words used by Iwen et al (2018) to describe the importance of the role of thyroid hormones in the regulation of body temperature. Thyroid hormones have both direct and indirect effects on thermoregulation.
The main thing one would want to regulate is T3, which is the functionally active form of the hormone, and so there are two ways of doing this:
The former is under fairly tight control by the hypothalamic-pituitary axis, which amplifies the signal of the handful of hypothalamic neurons that sense thyroid function. These cell bodies are generally said to sit in the paraventricular nucleus of the hypothalamus, which is a major thermoregulatory centre. The latter is mediated by the control of T4-5'-deiodinase, an enzyme that mainly resides in the liver and kidneys, and which is influenced by a whole host of factors, so diverse and poorly understood that even UpToDate authors waffle when it comes time to explain this regulatory step. In a rare show of respect for the reader's time and attention span, these regulator pathways can be summarised as follows:
Lastly, and at a risk of trespassing into Second Part Exam material where the pharmacological management of severe thyrotoxicosis is discussed, the reader is offered a short review of the drugs used to suppress overenthusiastic thyroid function, grouped by their mechanism of action: