25 November 2010

Inov-8 F-lite 230 Review

Unfortunately I broke my fibula in March (gymnastics) and did a lot of damage to the various talo-fibula ligaments in the process.  Those ligaments are still healing, and one part of my rehab is to do a lot of pseudo-barefoot work, mostly by wearing my Chaco sandles and Vibram KSOs during day-to-day activities.  At the very least, I am trying to restore proper biomechanics to my feet, if I have to go through all this discomfort!

However as winter approached I was feeling a little trepidation, since Vibrams are totally unsuited to -20 °C weather conditions with wind and snow.  The obvious pick, for me, was to look for some minimalist running flats and stuff some warm socks into them. I'm generally not willing to buy footwear without putting it on first (with the exception of thermo-molded footwear like ski boots), so I headed down to my local eclectic running store, FastTrax, and went through their stock of running flats.  Eventually the salesman let me try on the garish blue shoes on the top shelf, the Inov-8 F-lite 230s, which I immediately liked.   They are so named for their weight, the shoes as a pair weighs in at 230 grams, or about half a pound. From what I can tell, I'm pretty damn lucky to be able to try these on in a store in Canada as they seem to be hard to find outside of the UK.
'Garish' describes the vivid blue colour quite well
The F-lite 230s is marketed as a 'mountain running flat.'  I consider them an ultra-light approach shoe. The lugs on the sole are made of sticky climbing shoe rubber, and they are quite pliable.  The heel-lift is probably 3 mm, which makes them pretty much the flattest true shoe I've ever owned.  I found them to be immediately comfortable out of the box.  The heel box is especially effective in trapping my heel and because the sole is so flexible, there's no noticeable sliding of the heel when walking or running.  These shoes are very flexible: it's easy to twist them through 180° or touch the toe to the heel.

The upper is composed of mesh, but the laces are then vertically reinforced by a pliable plastic that helps distribute the forces better so the upper doesn't collapse onto your foot.  I think this is a good design decision for light-weight uppers as compared to just a velcro strap. 

The most 'non-barefoot style' features of these shoes is: 1.) their general squishiness, and 2.) the pointed, low-volume toe-box. 

I find the pointed toe-box a little strange.  I probably sized these shoes half-a-size too large as a result; according to the Inov sizing chart I should be wearing size UK6.5 but I actually have size UK7.5s.  Realistically, I should probably size for UK7.0.  The pointed toe-box does seem to expand out without really putting pressure on my toes, so that's something to consider.  I also remember my Vibrams were tight in the right big toe (my right foot is longer than the left) as well and they stretched out.

The shoes also have quite a thick (3 mm) and squishy insole.  They can be removed of course, but for now I'm using them. In general if I take the insoles out and just walk around the shoes do not feel nearly as squishy anymore.  If I did try to size down into a UK6.5 shoe, I would probably take the insoles out in the store.  The finishing of the midsole isn't free of stiching so these shoes probably can't be worn sans insole and sans socks.

The last drawback of these shoes is that the lugs, being composed of climbing rubber, aren't super durable.  Inov does have very similar shoes with harder wearing rubber compounds, but I didn't have any choice of models in the store.   

It's sort of difficult for me to properly review these things given how I can't really run properly yet, but I have been running in them three times now.  Twice was just running to school (about 2 km), which is on pavement.  I do not heel strike in these shoes on pavement, even with my limited range of motion in my right ankle.  The third time was a trail run at the bottom of the scramble shown in the above picture, and they performed spectacularly well in the soft trail.  Foot sensitivity is not as apparent as in the Vibrams, in that small pebbles are unnoticeable but the larger rocks and branches are still felt through the flexible sole just fine, and the lugs make them  grip far better in soft ground. 

Up on 'Vision Quest' in the David Thompson range.
I have to say, Inov has a very extensive stable of minimalist running shoes designed for natural activities.  I find their product line personally pretty compelling (in that I sort of want to buy one of each).  If you like hiking and other non-road running activities, go take a look at what they offer on their website.  I hope that my local shop brings in some more models, and hopefully I can try a smaller size come summer-time.

16 November 2010

Photovoltaics: Multiple Electrons from one Photon

 A month ago a report appeared in Science magazine on a new prototype solar cell that could produce more than one electron, a packet of electrical energy, from one photon, a packet of light energy.  This trick isn't new, I discussed a bunch of such concepts years ago in a post on quantum photovoltaics. What's new is that Samber et al. report in "Multiple Exciton Collection in a Sensitized Photovoltaic System," have achieved high efficiency in this process.

The typical goal for these sort of 'quantum' solar projects is to better match the wavelengths of light the photovoltaic system can absorb to that of the spectrum of light that is produced by the sun (and filtered by the atmosphere). The theoretical limit for Silicon alone in a photovoltaic system is 33.7 %, which is known as the Shockley-Quiesser limit. Of course, most commercial PV systems are only around 12 % efficient or less, so there is still considerable room for growth.  An example of such a spectrum-matched system is Spectrolab's space photovoltaics, which are actually stacks of multiple photovoltaic systems all operating at different wavelengths, and achieve roughly 30 % efficiency in a commercial product. 

 Figure 1: The air-mass 1.5 standard spectra (indigo line), which is an estimate for the spectra that arrives at the Earth's surface after passing through the atmosphere.  The red line is the band-gap for Silicon; for longer wavelengths (red-er) Si cannot absorb the photon.  For shorter (blue-er) wavelengths the extra energy is lost.
If you could get one electron out from a infrared photon and two from a blue photon, then the energy gained is fairly significant.  This result has been reported on before, but in this paper, for the first time, the overall system produced more electrons out than photons in, as observed to just isolated nanoparticles.  In photovoltaic parlance, the number of electrons produced per photon is known as the quantum yield, but this doesn't describe how many electrons actually escape and result in electrical current.  That quantity has the wordy name, absorbed photon-to-current efficiency.

Figure 2:  Absorbed photon-to-current efficiency (APCE) as a function of wavelength for the described cells.  The x-axis  is in electron volts, to convert to wavelength, divide 1240 nm by the photon energy [Fig 4. from Sambur et al., 2010].

Overall,this would be a really interesting paper except for one obvious drawback: the active layer of quantum dots is really really thin.  There's only a single layer of quantum dots and given an average diameter of 10 nm, that's not very think for visibile light.  Compare that to a standard Silicon cell being hundreds of microns, or a thin-film cell at 10 μm which is still a thousand times thicker. In fact it's so thin that they absorb only 1-2 % of the incoming light. 

Since the problem with quantum dot strategies is always getting the electrons out, and not absorbing the light, I'm not sure that this work will have a great impact when scaled up.  At the very least, however, it does show that it's possible to build a quantum dot solar cell that works as advertised, producing more than one electron per photon, and doing that quite well.

09 September 2010

Schizophrenia and Vitamin D

 A recent short article published in the Archives of General Psychiatry by McGrath et al. (2010) highlights that abnormal vitamin D status in newborn babies is a predictive factor for developing schizophrenia later in life.  The study was conducted on 424 patients and 424 controls, all born in Denmark since 1981.  Presumably the population the data set was constructed from was very large if they were able to find 424 babies who later developed schziophrenia. 

The key finding is that the risk of schziophrenia has a U-shaped curve with neonatal serum concentration, which is illustrated in figure 2 of the article.The findings were statistically significant with a maximum relative risk of 2.1 for having very low vitamin D status compared to the optimum level.

One figure that's sadly lacking from the publication is a histogram of the entire population for vitamin D serum concentration.  Since Figure 2 is only given in percentiles, we cannot evaluate what the actual optimal vitamin D concentration is, nor what is too high.  I think this is a major oversight in this article. 

The potential links between the general family of autism, schizophrenia, and bipolar disorder and vitamin D deficiency have been hypothesized before, such as in this article from the Vitamin D council.  Obviously, with a relative risk of 2.0 vitamin D isn't the whole story here, but it likely plays a role in the regulation of brain development.  The question is how?  Is it a precursor hormone to a development hormone?  McGrath referenced an earilier article (on which he was also an author), Eyles et al. (2005) which suggests that vitamin D plays a direct role as a paracrine hormone in the mammalian brain.

28 July 2010

Gone Paddling

So I'm off to Portland, Oregon for a staid conference and a little fun (hopefully) on some of the copious Oregon rivers.  Of course on the drive down I'm stopping off in Fernie, BC so I'll have some fun for sure.

I realize the old blog hasn't been getting a lot of attention in the past few months.  Basically, I'm busy enjoying my summer and working hard on my Ph.D. program so I really haven't had a lot of spare time on my hands.
I'll be back, it's just that blogging in a purely altruistic activity for me, so something it gets pushed way back on the priority list. If you haven't already done so I would respectfully suggest you use some sort of subscription service, such as Google Reader, to watch my blog.

Meanwhile, some pictures of what I been doing this summer for your enjoyment:

Surfing the Brierlies hole on the North Saskatchewan, near Rocky Mountain House.

A straight-forward little drop on the Castle river, pretty much the only shots I have of me running rapids.

Edging through the rolling waves.

The Mistaya river at low water, at the junction of Jasper and Banff National Park.

The Portage rapid on the Kicking Horse near Golden.  The scale is a little deceptive here, those waves are about as tall as a person.

The float before the fun part of the Sunwapta river in Jasper National Park.

I seem to see an absurd number of double rainbows on my travels.

 Watching for swimming beginners on the Whirlpool river in Jasper National Park.

Sadly, as things get more difficult in whitewater, the tendency to take pictures drops off, so not too many really fun pictures here.  Maybe I should get a helmet camera...

05 May 2010

Blog Format Change

I changed the format of the blog last weekend to allow me to incorporate some widgets more easily.  I still have to do a lot of boring HTML work here.

I am having some trouble figuring out how to get the post body and sidebars to fill the screen instead of just the middle third.  My old template was so much different in terms of HTML coding.  If anyone has a clue how to do this easily within the template XML, please let me know.

Vitamin D Reduces Premature Births

So on the new front for Vitamin D supplementation it appears that maintaining high levels of vitamin D greatly reduces the risk for premature births (hat-tip to Sharon Kirkey of the Ottawa Citizen).  Supplementing with 4000 IU of vitamin D per day compared to 400 IU per day reduces the risk of a premature birth by half.  This may have to do with the role of vitamin D in the innate immune system.  Previous research published in the New England Journal of Medicine found that around 25-40 % of pre-term events may have been caused by vaginal infections (Goldenburg et al., 2000). 

This research isn't published in a peer-reviewed journal yet but rather was presented at the Pediatric Academic Societies meeting in Vancouver, May 1-4.  I did, however, manage to track down the abstracts for the conference:

[1665.6] Vitamin D Supplementation during Pregnancy Part 2 NICHD/CTSA Randomized Clinical Trial (RCT): Outcomes

Carol L. Wagner, Donna Johnson, Thomas C. Hulsey, Myla Ebeling, Judy Shary, Pamela G. Smith, Betty Bivens, Bruce W. Hollis. Pediatrics/Obstetrics, Medical University of SC, Charleston, SC.

BACKGROUND: Vitamin D (vitD) deficiency during pregnancy is a serious public health issue, affecting mother and fetus. Establishing optimal vitD requirements of pregnant women is vital in preventing vitD deficiency and its health-associated comorbidities.
OBJECTIVE: Evaluate the effectiveness of high dose vitD supplementation in decreasing pregnancy comorbidity risks.
DESIGN/METHODS: Following their consent, pregnant women 12-16 wks' gestation were randomized into 1 of 3 tx grps stratified by race: 400, 2000 or 4000 IU vitD3/day until delivery. Women were evaluated for safety (Abstr#750939), efficacy and effectiveness with monthly 25(OH)D; 1,25(OH)2D; serum Ca, Cr, phos, and urinary Ca/Cr levels, all measured using standardized methodology. Comorbidities of pregnancy (preeclampsia, gest diabetes, any infection, preterm labor (PTL)/preterm birth (PTB) <37 wks GA) were recorded prospectively for each subject. Investigators and health team were blinded to tx grp.
RESULTS: Of the 494 women who enrolled in the study, 350 women continued until delivery: 98 African American (AA), 137 Hispanic (Hisp) and 115 Caucasian (Cauc) women; with 111 controls, 122 in 2000 IU and 117 in 4000 IU groups. There were no differences in baseline vitD status between dose groups. The mean 25(OH)D by dose group at delivery, as chronic level, and 1-month before delivery were significantly different between control and 2000, control and 4000, and 2000 vs. 4000 (p<0.0001). 25(OH)D had a direct influence on 1,25(OH)2D levels throughout pregnancy (p<0.0001) with 25(OH)D of 40 ng/mL required to obtain maximum 1,25(OH)2D production. In bivariate analyses controlling for race, PTL/PTB and infection were inversely related to 25(OH)D and were lowest in the 4000 IU grp (p<0.0001). In logistic regression, comparing 400 vs. 4000 IU and controlling for race, the risk of comorbidities were 0.50 (CI 0.27-0.95; p=0.03) among those in the 4000 IU grp. Using least sq means, when adjusting for race, 25(OH)D of women with comorbidities was 33.4 ng/mL compared to 39.0 ng/mL in those women without (p < 0.008).
CONCLUSIONS: VitD sufficiency was strongly associated with decreased risk for PTL/PTB and infection during pregnancy and comorbities of pregnancy, with the greatest effect with 4000 IU vitamin D/day regimen. Therefore, to attain a minimal 25(OH)D level of 40 ng/mL, we recommend 4000 IU/day for all pregnant women.E-PAS20101665.6
Not that infection rates were inversely related to serum vitamin D levels.

Now, there used to be concerns over whether high vitamin D levels could cause birth defects related to calcium metabolism.  The researchers found these claims to be baseless.

Vitamin D Supplementation during Pregnancy Part I NICHD/CTSA Randomized Clinical Trial (RCT): Safety Considerations

Carol L. Wagner, Donna Johnson, Thomas C. Hulsey, Myla Ebeling, Judy Shary, Pamela G. Smith, Betty Bivens, Bruce W. Hollis. Pediatrics, Medical University of SC, Charleston, SC.

BACKGROUND: Vitamin D (vitD) deficiency during pregnancy is a serious public health issue that affects both mother and fetus. Establishing the optimal vitD requirements of the pregnant woman is vital in preventing vitD deficiency.
OBJECTIVE: Evaluate the safety of high dose vitD supplementation during pregnancy in a RCT.
DESIGN/METHODS: Following their consent, pregnant women 12-16 wks' gestation were randomized into 1 of 3 treatment (tx) groups (grps) stratified by race: 400, 2000 or 4000 IU vitD3/day until delivery. Women were evaluated for safety, efficacy and effectiveness with monthly 25(OH)D; 1,25(OH)2D; serum Ca, Cr, phos, and urinary Ca/Cr levels, all measured using standardized methodology. Investigators & health team were blinded to tx grp.
RESULTS: Of the 494 women who enrolled in the study, 350 women continued until delivery: 98 African American, 137 Hispanic and 115 Caucasian women; with 111 controls, 122 in 2000 IU and 117 in 4000 IU grps. There were no differences in baseline 25(OH)D by dose grp. The mean 25(OH)D by dose grp at delivery, as chronic level, and 1-month before delivery were significantly different between control and 2000, control and 4000, and 2000 vs. 4000 (p<0.0001). 25(OH)D had a direct influence on 1,25(OH)2D levels throughout pregnancy (p<0.0001). Throughout the study, there were no differences between grps on any safety measure: serum Ca, Cr, urinary Ca/Cr ratios (pNS between grps). Not a single adverse event was attributed to vitD supplementation by the DSMB. Neonatal 25(OH)D was significantly correlated with maternal 25(OH)D overall, 1-month prior and at delivery (r2=0.6; OR 0.50); and was significantly different by tx group: 18.2±10.1 (control), 22.8±9.8 (2000 IU) and 26.5±10.3 ng/mL (4000 IU), (p<0.0001).
An interesting pair of abstracts to be sure.  I look forward to seeing the data for myself when it's published.

23 April 2010

Silicon Nanowire Photovoltaics

In the 14 February 2010 issues of Nature Materials, Kelzenburg et al. report on their progress in developing a photovoltaic cell composed of an array of Silicon nanowires: Enhanced absorption and carrier collection in Si wire arrays for photovoltaic applications.  Also see the supplementary information on the fabrication process.

Theoretically an array of nanowires has some advantages over flat or patterned silcon when it comes to light trapping and absorption. The disadvantages come from difficultly in getting the electron-hole pairs out of the wires, both in having sufficient conductivity of the wires and a good electrical contact to the outside world. On the negative side using patterning requires some sort of controlled deposition onto the thin-film substrate when ideally you would like to use some sort of self-assembled system that doesn't require a carefully patterned mask and has a huge through-put for manufacturing.

Figure 1 from (Kelzenburg et al. 2010): (a) SEM image of regular nanowire array embedded in PDMS and (b) schematic of system.

The arrays in question are rods 8-12 μm long that cover 5 % of the areal density of the surface. Let's compare that to a wafer-type Silicon photovoltaic cell, which might have 250 μm of high-quality Silicon in it, the Silicon nanowire PV cell is using about 0.24 % as much material. Since photovoltaic-grade Silicon is quite expensive, this is potentially a cost advantage. From a practical perspective, this concept is robust because the silicon nanowires are embedded in a polymer that protects them from damage.

The authors also added aluminium oxide (Al2O3) nanoparticles to the sides of their nanowires in an effort to increase scattering within the cell and hence light trapping. This had a very significant effect and they achieved a maximum of 84.6 % of light absorption compared to 87.2 % for a commercial cell. Remember this is with a tiny fraction of the amount of Silicon used in a commercial cell.

Figure 4 (from Kelzenburg et al., 2010):  Compare the solid red to solid blue lines in (a).  The nanowire arrangement is slightly inferior in the visible spectrum but is markedly superior in the near-infrared.  In (b) area under the curves indicates total light absorption and hence electron generation.

Designing the film so that the nanowires were oriented in a regular, periodic pattern gives a high packing fraction, thereby enhancing light absorption, but it also results in certain orientations being 'dead zones' where light is not well absorbed. In particular, when the rods are facing the sun dead-on, they do not absorb well. However, the regular array of wires would be well suited to situations where the photovoltaic panel was always oriented away from the sun, such as vertical mounts on a wall or horizontal mounts on a flat roof.

Lastly, it was reported at the end of the supplementary information (where better place to hide such details?) that they saw some evidence of sub-bandgap absorption.  That is, light longer than 1120 nm was being absorbed.  This isn't supposed to happen and it tends to reflect parasitic absorption that doesn't contribute to moving electrons (and in fact reduces the output current).  Thus there is some concern that the increase in infrared absorption — the main claim to fame here — was due to parasitic effects rather than something that would actually enhance the electric current being produced. They did not, however, find that all of their cells had sub-bandgap absorption so it may be largely a quality control problem.

22 March 2010

Chronic forms of Euthyroid Sick Syndrome and Non-Thyroidal Illness

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:
  1. the hypothalamus/pituitary gland, which controls the negative feedback of the system and regulates the thyroid through thyrotropin (TSH);
  2. the thyroid gland itself, which produces thyroxine (T4);
  3. 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;
  4. 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.

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 T3.  Many tissues have the ability to convert T3 to T4, but the hypothalamus isn't one of them. It is reliant on other tissues to produce T3. 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 T3 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 T4, 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 T3 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 T4 levels.  If an infection lasts a long time, then overall T4 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
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 (T4) 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 T4 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 T4 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 T4 to T3 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 T4 to T3 and can also deiodinate rT3, so they cooperate as the on-switches  Type 3 deiondinase (D3) deactivates T4 to rT3 and both types of T3 to T2, 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 T3 to T2, 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 T4 in testing for thyroid disorders.  Thus the two principle requirements for maintaining a normal body temperature are:
  1. Sufficiently high concentration of circulating T4 in the blood.
  2. 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)
Effect on D1 activity
Effect on D2 activity
Increases (tissue specific
– liver)
Increases (tissue specific
Trivial increase
Growth hormone (GH) &
Insulin-like growth factor (IGF-1)
Increases ratio of T3 to T4 and reduces rT3; could also be down-regulating D3
likely similar to D1
Thyrotropin (TSH)
Up-regulates thyroid D1 indirectly
Cytokines (i.e. ‘inflammation’)
Cold exposure

Reverse T3 is an interesting molecule that could potentially cause a lot of problems if the balance of T3 to rT3 was overly altered.  It acts as a highly competitive inhibitor for the T3 in DNA transcription, which means it gets into T3 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 rT3 from T3 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 rT3 by transforming it to T2 so it is not clear at all whether rT3 can cause physiological problems.  When considering D1 alone there should be some steady state quantity of rT3 in tissues that are served by thyroid and liver-derived T3.  I personally suspect rT3 is involved in the local regulation of T3, in that it prevents local tissues that produce T3 for export to the body from overwhelming their oxygen and nutrient supplies. 

I did find one mention for potential pathology for rT3 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 T4 to rT3 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 (R2 = 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 T4 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 T3 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 T3 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 T3 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 T3 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 T4 and 0.3 % of T3 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 T4 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 T4 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.

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.

13 March 2010

40 % of Celiac Patients have Anti-Pituitary Gland Antibodies

In 2006, an Italian group noted that children with celiac disease often suffered from failure to thrive (i.e. they were short and slight) (Iughetti, 2006). They were able to link this to a deficiency in growth hormone, which is produced by the pituitary gland. Now, growth hormone itself doesn't regulate bone growth, but insulin-like growth factor-1 (IGF-1) does and it is regulated by growth hormone. After removing gluten from the diet, most children had a growth spurt and caught up to their peers but seven did not. Those that didn't catch up were then tested for anti-pituitary antibodies, and five of the seven presented them.

Now 5 of 7 is not a sufficient statistical sample, so the group went back to work over the next three years and tested for anti-pituitary antibodies in many of their newly diagnosed celiac patients (all children) (Delvicchio, 2009, also see editorial by Fasano, 2010). 50 of 119 (42 %) tested positive for anti-pituitary antibodies. There is an interesting comment by Delvicchio to the extent shortness can appear independently of the destruction of intestinal vilae,
It is well established that short stature can be the only presenting clinical feature of CD (31) and in unselected cases admitted for short stature, the prevalence of CD reaches 8%, CD being by far more common than GHD or any other organic disorder. The pathogenesis of CD-associated short stature is still unclear and although growth retardation has traditionally been attributed to generalized or selective malnutrition, new insights on its pathogenesis are emerging.
This suggests that something like one in ten children who are short are short because they eat wheat (notwithstanding selection bias). This isn't the first time autoimmune disease of the pituitary gland has been linked to stunted growth either. A child with lymphocytic hypophysitis (including diabetes insipidus) was previously found to have the same bone-age retardation symptoms as the celiac patients (Weimann, 1997).

The pituitary gland is a small bulbous organ that sits at the base of the brain smack dab in the middle of the skull. The pituitary is often called the master endocrine gland, but it is in turn is controlled by the hypothalamus, a portion of the brain that is the nexus of the autonomic nervous system. The hypothalamus, the posterior pituitary, and the anterior pituitary can all be considered to be different tissues of a single organ system often called the hypothalamic/pituitary axis. Because the pituitary controls such a diverse set of endocrine tissues, if something goes wrong with the hypothalamus/pituitary axis the symptoms can be very diverse. Furthermore, the area is small, located in the center of the skull and hence largely impossible to safely biopsy.

Like other endocrine organs, the pituitary can be victim to the helper and killer T cells of the adapted immune system. This condition is typically called lymphocytic hypophysitis, but also autoimmune hypopitutarism, and typically affects the anterior pituitary which is the hormone-producing portion of the pituitary (Rivera, 2006). The neural portion of the pituitary, the posterior portion, can also be affected and this typically causes diabetes insipidus through arginine vasopressin deficiency (not to be confused with the insulin disorder diabetes mellitus). Autoimmune disease of the pituitary gland is thought to be quite uncommon, with a series of 2500 surgical cases finding an incidence of 0.24 % (6 of 2500) (Sautner, 1995).

Although the Italians appear to have examined primarily growth hormone deficiency, lymphocytic hypophysitis usually results in more than one hormonal deficiency. Rivera (2006) notes in a review for lymphocytic hypophysitis that 60-65 % of cases have ACTH deficiency, 47 % have TSH deficiency, 42 % have gonadotropin deficiency, 37 % growth hormone deficiency, and 34 % prolactin deficiency. For those of you who aren't familiar with the hypothalamus/pituitary hormones I present the following summarizing table:

Table 1: The hypothalamic/pituitary axis hormones and their actions on the human body.

Hypothalamus/Pituitary hormones


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 study did test for thyrotropin (TSH) and didn't find any significant association between anti-pituitary antibodies and basal metabolic dysfunction at the hypothalamus/pituitary axis. However, some 10 % of the patient population did have thyroid disease which is far above the general population average (of around 1 %). Hypophysitis tends to develop over time, with more and more functions being damaged, so these results may simply be representative of the young age of the patients (average age was ~ 6 years old).

In general, persons with one autoimmune disorder are at much higher risk to develop other immune disorders. It would take more effort and text to explain why this is than I'm willing to expand here so I will simply claim this is a fact. It seems that Iughetti has been on the case of co-morbid endocrine disorders associated with celiac disease for quite awhile (Iughetti, 2003). If you go to the Wikipedia page for gluten sensitivity you will see an entire section on "idiopathic gluten-sensitivity." A lot of this could possibly be traced back to autoimmune disease of the pituitary gland.

I recall that something like 12 % of the general population present anti-gliadin antibodies (gliadin being the offending peptide found in the wheat gluten protein). Celiac disease is only one manifestation of gluten sensitivity and I am quite certain that we will continue to see new conditions linked to gluten sensitivity over the next couple of decades. The secondary plant compounds found in the wheat plant's seed seem to be quite harmful to humans and in my opinion wheat is not suitable for human consumption. Plants, after all, cannot run away so they must rely on armour and toxins to stop animals from eating them. Anyone suffering from an unknown condition that presents as a disrupted hormonal milleu should strongly consider the shotgun approach of a paleolithic diet as a potential solution.