Tuesday, February 28, 2012

Zinc Deficiency and Children with Autism

Thanks to a commenter for pointing me to a newish study (open access):  Infantile zinc deficiency: Association with autism spectrum disorders.

I see Paul Whiteley already covered it here.  If you are interested in the autism spectrum disorders, I very highly recommend his blog.  Paul is very sober and clear-sighted about the limitations of the research information but has an open mind about what might be clues to the pathophysiology of these disorders.  Since it is a long paper, and Paul and I have quite different styles, I think there is plenty of room for my own thoughts.

Atlas Genius:  Trojans (right click to open in new tab)

In this study, nearly 2000 children with autistic disorders had hair tested for zinc deficiency.  584 (29.6%) subjects had levels lower than two standard deviations below the mean of the reference range.  43.5% of the male children ages 0-3 and 52.5% of the female children 0-3 in the sample were zinc deficient.  Older children with autism in the study had a lower incidence of zinc deficiency, which continued to decrease with the age of the subject sample, to the point where autistic children over the age of 10 had normal zinc levels.  Normal hair zinc in healthy children appears to be around 130 ppm, and one autistic 2 year old in the study had a level of 10.7 ppm.

However you slice it (and let's take into account the limitations of a strictly observational study), that is an impressive finding.  The authors speculate that epigenetics could be a factor in the pathophysiology of autism.  Epigenetics is the alteration of gene expression by environmental influences.  Mineral deficiencies could certainly alter gene expression and perhaps cause an epigenetic disorder.  The other side of the argument is that active inflammation and stress causes us to waste zinc (and other minerals) as part of the inflammatory process.  Since we know autistic spectrum disorders are related to inflammation, it would make perfect sense that babies and toddlers with autism would have low zinc levels.  Low serum zinc also seems to be associated with heavy metal toxicity, which is also associated with autistic spectrum disorders (more often cadmium and aluminum, according to the study authors, than mercury).

But measuring a mineral deficiency is more tricky than it might appear.  Zinc can be sequestered in the bones or liver and bound up by protein in the serum.  Zinc levels can vary considerably based on infection, stress, low protein levels in the blood, and even time of day.  Hair levels could perhaps be considered a more reliable indicator of full-body zinc stores, so may be a more useful measure for these sorts of studies.

Zinc deficiency could very plausibly be part of what causes the symptoms of autism.  Zinc plays an important role in protein synthesis, cell growth and repair, and levels need to be super topped off in pregnant women and infants where all these processes are occurring at a more rapid rate than any other time in one's life.  Also, we know that a "leaky gut" has been associated with autism in a rather well-designed study, and with leaky guts there is malabsorption of nutrients and minerals.  Many children with autism have signs from birth (when everyone has a leaky gut, up through 6 months of age when there is no argument that exclusive breastmilk is best, period), but some children seem to develop normally and do not exhibit symptoms until later.  Could leaky guts leading to toxin exposure, and micronutrient deficiency have something to do with these cases?  Seems a plausible theory.

In addition, in the setting of zinc deficiency, the intestinal zinc importer (the awesomely named Zip4) is upregulated, sensibly enough.   Increasing Zip4 can increase the absorption of toxic heavy metals such as cadmium and lead.  Therefore an early zinc deficiency could plausibly lead to more absorption of toxic metals.   (Creepy fact from the article:  soy-based infant formulas have 6 times higher cadmium levels than cow's milk formulas, and cereal-based formulas 4-21 times higher levels (1).)

I don't think there is any argument that we all need sufficient zinc, particularly pregnant women and babies.  As far as I know, there are no controlled studies of zinc supplementation in pregnant women and babies and autism risk, so we really can't make any conclusion or recommend any sort of increased zinc supplementation in babies at this point.  There is more data in ADHD and I should probably pull those papers myself (some of them are too old to pull easily) and do a post on it.  Super-high zinc intake has killed older people who used zinc-based denture cream by causing copper deficiency and heart arrhythmia, and babies and little children (like the elderly) will be more vulnerable to these sorts of insults.

More data please!  Researchers, rescue us from the rocky shoals of the unknown.

(Hmmm.  My favorite diaper cream is zinc-based.  I wonder how much is absorbed and if that has any bearing on zinc levels, zinc deficiency, etc.)

Sunday, February 26, 2012

Thyrotropin Day to Night

It's a chilly Sunday morning.  More plowing away at the endocrine system, and now I remember why endocrinologists can be cranky sometimes.  Gads it is complicated, but beautiful.

Two music selections, one for those who prefer a xanthine alkaloid jolt of rock:

Kasabian Reason is Treason

The other for those who like to let Sundays wake them up, sunshine through the window style:

Dance of the Blessed Spirits (from Orpheus and Eurydice)

I don't recommend listening to these simultaneously.

Oh, in the northern hemisphere we've been having a lovely show of the planets the past couple days.  They are exceptionally bright, with reports of seeing Venus in broad daylight.  (Here is a picture from @BadAstronomer through his binoculars).  Last night, just after sunset (lower right), I snapped this picture with my phone of the crescent moon and Venus (through the trees) with Jupiter above to the left:

All right.  Enough putting off the inevitable.  Endocrinology!  As we know from a previous post, thyroid hormone secretion is regulated (to some extent) by a classic negative feedback mechanism.  Thyrotropin (TSH) is released from the anterior pituitary and then travels down to the thyroid to stimulate the TSH receptor (TSH-R).  This action leads to the release of thyroid hormones, mostly T4 but some T3, which toodle on up to the pituitary and inhibit the production of TSH.  We also learned in previous posts there is other master regulation via the hypothalamus and TRH as well as regulation at the tissue level by how readily the prohormone T4 is made into the active hormone T3.

In the serum, T4 and T3 levels remain relatively stable during the course of 24 hours.  However, at a cellular/nuclear level it is hard to say what is happening at any given time.

TSH secretion from the pituitary, on the other hand, varies considerably, as demonstrated by a graph from this paper which is available free full text on Pubmed (showing some differences in TSH secretion variation between lean and obese women):

In fact, TSH is one of the well-known hormones, such as cortisol, melatonin, prolactin, etc. that change as part of the daily circadian rhythm.  TSH peaks during the night and remains lower during the day.  The fact that serum T4 and T3 levels remain relatively constant despite this change is intriguing, though again, there is likely a good deal of regulation we don't understand and that is difficult to measure at an intracellular level, and it may have to do with some of the regulation I talk about in a couple of paragraphs.

A bit of a side note but one that may be of interest for the future when we take a peek at the alternative medicine diagnosis of "adrenal fatigue," the circadian rhythm peaks seem to be delayed by an hour or two in folks with seasonal depression, premenstrual dysphoric disorder, and major depressive disorder.  Treating the depression with late sleep deprivation (i.e. going to bed at 9 or 10 and waking up at 1am) seems to jerk the cortisol portion of the rhythm back to normal, and in some studies, the TSH and prolactin as well (I'll discuss these and link the reference studies in the future posts).

Here is where we get to an even more complicated part.  TSH is not just "TSH."  As TSH is created and as it is secreted, we add various numbers and types of carbohydrate molecules to the protein hormone to make a glycoprotein (p 84-6).   These carbohydrate molecules help with the creation and proper folding of the protein into its final active shape.  TSH is then a group of "isohormones" with different carbohydrate compositions.  People with hypothyroidism have an increase in sialylated TSH which decreases when the hypothyroidism is treated with T4 hormone. (Sialylate is one type of  carbohydrate molecule that can be plopped onto TSH.  Sulfated carbohydrate is another).  Higher sialylation is also seen in the nocturnal surge of TSH in normal patients compared with the daytime circulating TSH in the same person.  In mice, as the hypothalamic-pituitary-thyroid axis develops and matures, there are higher proportions and more complex carbohydrate molecules on the TSH backbone.

Phew.  Cowboy Junkies:  I'm So Open

What are all these carbohydrates doing?  Besides helping out with the folding and secretion of the protein, they also seem to modify the biologic activity of TSH.  If we take TSH and apply enzymes to it to clean off the carbohydrate molecules, TSH will still bind to its receptor, but its activity is very much reduced.  Increased sialylation seems to moderately reduce the activity of TSH at the receptor as well, at least in the test tube.  In the body, the highly sialylated TSH lasts longer than the less sialylated versions, so overall the sialylated form will cause more receptor activation (though it is less potent, it lasts longer).  High-mannose versions of TSH seem to be more aggressive about stimulating messaging through the cell after alighting upon the TSH receptor and activating it.

I know.  See how one can be led down the garden path with respect to understanding something about hormonal regulation, but then you find a whole 'nother layer of complexity that boggles the mind.  Sialylation to sulfation ratios of circulating TSH affect metabolic activity and clearance, but these activities are also dependent upon the location on the TSH where the carbohydrate molecules are added (they can be added at all sorts of different places on the various protein subunits and frequently are).

These hormonal systems have developed over thousands of millennia of evolution, and it is only in the very recent past that we have understood much of any of it.  The spectacular dance of molecules and the exquisite microregulation is humbling, to say the least.  How much is changed by nighttime lighting, by inflammatory signals, by activity and rest?  Appreciation of the complexity is what makes me try, in a practical fashion, to emulate the diet and lifestyle of the paleolithic past, as it seems likely the best way to keep the system acting at optimal capacity.  That's just a hunch, but I think the null hypothesis that begs to be disproven.

Thursday, February 23, 2012

Meatless = Less Tense in the Short Term

Hi!  Back to the thyroid in a bit… but I've had a few questions about a study that came out earlier this week so I thought I would do a quick post.

Restriction of meat, fish, and poultry omnivores improves mood: a randomized controlled trial

The Strokes: 12:51 (video starts with an ad.  Sorry!)

This pilot study was small and interesting and embarked upon to try to answer some questions about diet and mood.  Hooray! Specifically the authors speculate that the arachidonic acid (AA) in meat could impact how we feel, and that restricting AA could make us feel better.   AA (which is a highly unsaturated omega 6 fatty acid) is situated in the biochemistry to be pro-inflammatory (though WAPF has some issues with this characterization).  Specifically, AA eaten directly competes with the desaturating enzymes for EPA (a long chain omega 3 fish oil constituent), so AA could potentially increase pro-inflammatory cytokines such as TNFalpha which are known to have mood altering effects.  One question is does fish consumption ameliorate the affects of pro-inflammatory AA, and is that why populations who eat fish tend to have better moods than those who don't?  Hey, let's whip up a little experiment and get informed consent and run it by the IRB and test it.

So… 39 adults who ate meat or poultry once daily (thus omnivorous) with no major psychiatric problems, substance abuse, or health problems were randomized to three groups for two weeks.  One group was told not to change their diets (OMN).  Another group was told to avoid meat and poultry but to eat fish 3-4 times a week (FISH).  The last group was told to avoid all animal products except dairy (VEG).  (Traditionally in the US eggs are considered dairy for whatever reason but I'm assuming they were left out as the yolks have a nice dose of AA).   Diets before and after were assessed by a "validated food frequency questionnaire."  The participants were also given a bunch of mood, anxiety, and depression rating scales before and after.

The results!  OMN and FISH groups were about the same with no change from baseline, but the VEG group showed a decrease in the psychological ratings scores with respect to tension and stress (anxiety and depression scores were not significantly changed).  Dietarily, if one can truly believe a report to a hundredth of a gram of dietary fatty acids based on food frequency questionnaires, EPA and DHA and AA dropped considerably in the VEG group, OMN group was unchanged, and the FISH group managed to increase their dietary long chain omega 3 fatty acid consumption by 100%.  They also successfully raised the O6/O3 ratio by 60% in the diet of the vegetarians, which I'm not enthusiastic about long term, by any means.

Hooray!  A result.  Decreased tension and stress.  But what does it mean?  I'm hoping this pilot trial is used as evidence to recruit funding for a bigger and more ambitious trial, because what these researchers did not measure is pretty much everything that would tell us anything about what actually happened to decrease those stress scores.  There were no measures of tissue fatty acids to tell us how the ratios changed in the body relative to these dietary changes, and no "after" measures of weight.   Losing weight from a diet is associated with improved psychological scores, and since vegetarian-geared fare is often healthier than the regular SAD meaty counterparts (tofurky and cheese pizza excepted), I wouldn't be surprised if the most dramatically altered diet caused more weight loss than the others.  Or it might have to do with changes in AA.  The Seventh Day Adventists study (which the authors if this study did as well!!) showed that "Vegetarian Diets Are Associated with Healthy Mood States."

(My critique of the SDA studies are that being part of a close-knit community that is very pro-vegetarianism is a HUGE confounder when it comes to mood and stress, and boy, it sure would be nice to know the tissue levels of fatty acids because that would tell us a lot more than just food frequency questionnaires and psych scales.)

We need more info to make anything of this little study.  I also think the title is misleading (and is leading to misleading news reports, as is typical), as actual mood and anxiety scores were unchanged, only the tension and stress scores (though certainly over the long term tension and stress are associated with more depressed and anxious mood states).  Whatever gets you funding, I suppose…

Sunday, February 19, 2012

Seasonal Variations in Thyroid Hormones

Just a little bit of an information post to get a handle on things and to open up some more lines of questions…in that vein:

This Head I Hold by Electric Guest (right click to open in new tab)

(Oh, be sure to look at the initial post for a short thyroid primer if you aren't up on your T4s, T3s, and TSHs).  

I'm having a little trouble nailing down consistent reports in the literature of seasonal hormonal variation.  The papers are old and often the studies were awfully small, and I'm also trying to get a handle on variations of thyroid hormones within the menstrual cycle, which might invalidate some of the results in the women in the studies if they were not controlled for stage of menstrual cycle. I'm not sure how important that is, however, as I can't find any consistent recommendations to measure TSH at a particular time of the menstrual cycle.  Estrogen will increase the amount of thyroid binding globulin, which will tend to bind up more T4 and T3.  With thyroid function especially the newest studies use far more accurate hormonal assays, but we just have to look at what the results say and keep an eye out for new studies.  One of the better papers is from the American Journal of Clinical Nutrition; "Seasonal variation in plasma glucose and hormone levels in adult men and women." 

According to some other papers linking this one, the results seem to be fairly consistent in several different studies of normal controls but not in folks with seasonal depression (1).  In short:

Fasting glucose levels are lowest in the spring and summer and highest in the fall and winter.  Accordingly, there are more diagnoses of new cases of type II diabetes in the fall and winter.  Fasting insulin was also significantly lower in the spring than in the fall.

Among the thyroid hormones, all people had normal levels through all seasons, but there were significant differences between the levels from season to season, and the levels also seemed to differ by sex.  All the measurements were taken in the morning after an overnight fast.

Total T4 was highest in the summer.  Free T4 was highest in summer and fall and lowest in the spring, with men having higher levels than women during the fall and winter and women having higher levels than men during the summer.  Total T3 was highest in the winter.  

There was a negative correlation between glucose and free T4, and a significant positive correlation between T4 and the amount of carbohydrate and sugar consumed.  The only major differences in eating across the seasons was an increase in sugar intake among men in the spring, and a lower fiber intake in men in the fall and in women in the winter.

The interesting thing is that in a study of 148 untreated men and women with depression, there were no differences in the thyroid hormones across seasons (though they did not measure the same people across seasons as it wouldn't pass the IRB to merely follow depressed people for a year without trying to treat them somehow).  

What does it all mean?  Well, let's start with going over how T4 becomes T3.  Both are made and released by the thyroid, though humans release about 15 times as much T4 as T3 from the thyroid (2).  In addition, some enzymes called deiodinases change T4 into T3 in the body, and this mechanism is the major one by which active thyroid hormone (T3) is made.   The deiodinases have a little pocket in them with a selenium molecule where the transformations occur.  Iron is also required along the way to make thyroid hormone.  

There are three types of deiodinases.  D1 and D3 live on the plasma (outer) membrane of cells.  D2 is within the endoplasmic reticulum within a cell.  D2 therefore creates active thyroid hormone much closer to the nucleus of the cell, where thyroid hormones exert most of their effects.  D2 is the most important deiodinase in the nerves and brain.  D2 has a very short half life (40 minutes) and its expression is tightly controlled.  Both high levels of T4 and reverse T3 can downregulate D2.  D2 is also the important go-between in how T4 levels regulate the amount of TSH secretion from the anterior pituitary (I know.  All endocrinology is like this, and understanding it is a bit like being a card counter in Vegas.)

D1 and D3, on the other hand, have longer half lives and seem to be more responsible for the serum (blood) circulating levels of thyroid hormones.  D1 makes T4 into T3 (though it can also inactivate T3), and D3 preferentially inactivates T3 by making it into reverse T3.  In times of iodine shortage or hypothyroidism, the brain can decrease the activity of D3 by about 90% while increasing the activity of D2, which leaves more T3 around a lot longer to protect the brain from an iodine deficiency.  Pretty cool.  In rats, when they are made iodine deficient, their serum and tissue T4 become almost unmeasureable, while brain T3 levels decreased only by 50%.  

A quick recap to solidify the facts in your brain:  D1 and D2 can make T4 into the active T3.  D3 makes T3 into inactive reverse T3.  D2 is found within the cell near the nuclear action, D1 and D3 on the surface of cells. 

So systemically, T3 and T4 levels remain pretty stable throughout the body, but intracellularly, depending on the actions of D2, T3 can be much higher.    In the liver and kidneys, without much D2, T3 at normal physiologic levels occupies about 50% of the nuclear thyroid hormone receptors (TRs).  In the central nervous system where there is a lot of D2, nuclear thyroid hormone receptor occupancy can be close to 95%.

D2 is also found in brown fat (which helps to regulate body temperature).  At room temperature, around 70% of the TRs are occupied by thyroid hormone.  In the cold, 100% of TRs are occupied.  Heat is generated in brown fat in part by uncoupling protein 1 (UCP-1), which is made in response to T3.  T3 also seems to increase the activity of fat-burning enzymes in response to cold.  It's important, however, to know that in these animal studies, the serum levels of T3 were relatively unchanged whether it was cold or room temperature.  All the action seemed to be happening intracellularly, with D2 then having tissue-specific metabolic effects by affecting the levels of T3 within the cells.  T3 changes within the cells may also explain changes in basal metabolic rate in response to different diets.  High carbohydrate diets in the context of eating too much (3), for example, may increase D2 activity in humans, who may have more brown fat than previously thought, and who also might have more D2 activity in skeletal muscle than previously thought.  Thyroid hormone is one of the few truly potent stimulators of metabolic rate.

All these findings elucidate an elegant system, wherein individual cells and tissues can respond to relatively wide variations in normal serum T3 and T4 levels.  It also shows us how we can preserve thyroid hormone function in times of iodine shortage.  On the other hand, it is hard to interpret some of these small variations in thyroid hormone function as the serum levels may have very little to do with what is going on within the cell, where all the action is.  Certainly in cases of severe iodine deficiency or thyroid disease or pituitary disease we can see the large and predictable changes in hormone levels and decipher their meaning and see how they will affect the physiology of the body.

The much smaller seasonal and nonthyroidal or euthyroid sick syndrome changes are much trickier.  What do we make of no significant seasonal differences in (serum) thyroid hormone levels in folks with seasonal depression, but a normal mild variation in healthy people?  Is that difference (a higher T3, perhaps) what makes us survive the winter with a smile?  I don't know.  We do know that in critically ill patients, tissue D3 expression is increased, thus reducing T3 and increasing reverse T3.  In fasting, a continuous administration of TRH can reverse the dropping T3 and T4 levels, suggesting that perhaps the central hypothalamic mechanism of reduced TRH in response to fasting (which can be reversed by leptin and feeding) may be more important than the peripheral mechanism.

Got that?  Heh.  There are consistent changes in summer and winter in thyroid hormone activity (but not in the disease state of seasonal depression).  These changes were not dependent on carbohydrate intake, though increasing carbohydrate does increase active thyroid hormone and fasting will decrease it.  If one thinks of an abundant summer and a lean winter, perhaps the increases in T3 in the winter is meant to compensate.  Would it compensate for a diet presumably lower in carbohydrate/plant matter in the winter?  Would it matter if humans evolved for most of the time near the equator?  Much of the study of thyroid hormone is done in reptiles (thyroid hormone is very important in stages of metamorphasis and reptilian development)--are these seasonal changes remnants of even earlier evolutionary signals? I don't think I have the breadth of knowledge to properly contemplate these questions.  

But I'll keep looking.  

Sunday, February 12, 2012

The Treatment of Depression with T3

Psychiatry is one of the few specialties where we are "allowed" to use T3 (the active thyroid hormone, instead of the safer prohormone T4) for treatment of resistant depression.  (Please see yesterday's post for a thyroid primer).  The literature for its use is extensive but old.  Much of it was done before there were very reliable lab tests for thryoid function, so symptoms such as pulse, insomnia, anxiety, palpitations and reflexes were measured to judge whether someone was made "hyperthyroid" with the treatment or not.  I suppose that made them bolder, back in the day (also, there were very few options, medication-speaking, so all the people studying resistant depression did a little study on T3.  For the same reason there is a ton of data on lithium for bipolar disorder. It was the only game in town for decades.)

In any event, I thought I would take the opportunity to catch up on the latest and greatest in T3 supplementation and safety issues, particularly since the very large STAR-D trial used T3 and found it equally efficacious in resistant depression to lithium use, and better than many other pharmaceutical tinctures.  Fortunately there is an up to date review from the Green Journal, T3 Augmentation in Major Depressive Disorder:  Safety Considerations.  The article had a number of interesting points, particularly with regards to the standard endocrinology method of treating hypothyroidism with T4 monotherapy.  I'll get to that in a bit.

All right.  So the weakness of most of the studies is that they were short, typically 2-12 weeks.  Also, most of them were studies of augmentation or acceleration with the old-fashioned antidepressants, the tricyclics (or TCAs).  And when I think of the tricyclics, I think of a cruder but much more medication-stringent time.  TCAs have lots of side effects (weight gain, dry mouth, fast heartbeat) and are fatal in overdose.  However, they are effective for many,  and folks with very serious depression where they were nonfunctional and suicidal who responded to the medicine would take them because being without proved worse than the side effects of being on them.  The SSRIs, with fewer (but still not insignificant) side effects had not yet been invented, and mildly depressed women were still being given B12 shots by their primary care doctors, who also advised them to smoke to give them energy and motivation.  (Or gave them a tiny bit of dexedrine in the morning and some barbituates at night.)

So we are dealing with a subset of very depressed people who do not respond to the tricyclics.  They don't seem to be hypothyroid by physical symptoms or the lab tests of the time, but a certain percentage would respond to augmentation with active thyroid hormone.  In addition, "accelerating" the tricyclics (which, like most antidepressants, take several weeks to kick in) with a dose of T3 up front (isolated to 2-4 weeks, then discontinued) seemed to work too.  There are fewer studies of augmentation with SSRIs, but these are also short and the results are less definitive.

Why would T3 help? What does T3 do in the central nervous system? Well, a lot.  The thyroid has fingers in almost every physiological pie, after all.  And T3 not only may act as a direct neurotransmitter, but it also seems to increase the efficiency of serotonin signaling, much like a modern SSRI.  T3 also enhances neurogenesis in the central nervous system and could also enhance noradrenergic signaling.  The conversion from T4 to T3 occurs all over the body, but in the central nervous system it uses different active genes than in the periphery and occurs within the cells.  These differences could explain my own clinical observations--that T3 augmentation seems to work best in folks already diagnosed hypothyroid that are on T4 monotherapy.  And the literature (such as it is) seems to support my observation (1).

(I am ignoring selenium and iodine deficiency for the moment as does this literature.  Much of North America has fairly selenium-rich soil except some of the Eastern Coastal plain.  Given the wide geographic distribution of vegetables and other produce, frank selenium deficiency is rare.  Also, with the advent of iodized salt, frank iodine deficiency is also rare so that babies are very rarely born with congenital hypothyroidism.  These facts do not mean that our selenium and iodine levels are optimized, but, again, I would say a frank deficiency is rare).

So the good news is that T3 augmentation seems to help some and (relying on some limited longer-term data up to several years) it seems to be relatively safe (particularly in the short term), though post-menopausal women need to watch the possible side effect of osteoporosis, and there is a continued risk of heart arrhythmia.  So in heart-healthy and strong-boned folks with a serious bout of depression, a small dose of T3 is a good option, even if they are clinically and by laboratory measure euthyroid (normal thyroid) particularly if they are the type to have serious episodes and then bounce back, rather than the more chronically low-grade depressed people.

The goal for longer-term treatment is to use a dose that keeps TSH at the low end of normal (or even somewhat below normal if there are no hyperthyroid symptoms) and free T3 at the high end of normal (I can tell you that the recommended dose of 25-50mcg almost always seems to overshoot this goal, but it probably reflects the long history of shorter-term studies), while monitoring bone density and cardiac side effects frequently, particularly in post-menopausal women.   T3 augmentation does seem to work better in folks with higher TSH and lower free T3s at baseline, suggesting we are, indeed, treating a type of "subclinical hypothyroidism" with depression symptoms, maybe those who convert T4 to T3 just fine in the periphery but who are poor converters in the central nervous system.  Again, this would support my clinical observation of long term treatment.  Fairly useless in the euthyroid except for temporary severe exacerbations, but useful in the hypothyroid or subclinical hypothyroid.

And what about those endocrinologists who are so very down on combination therapy with T3 and T4 for hypothyroidism?  I've had some tell me point blank (over the phone) there is no literature support for treatment of hypothyroidism with anything but T4 monotherapy.  I've had to pull out the "psychiatric indication" card and then they will back off, mostly because most folks in medicine are a little scared of psychiatrists and psychiatric patients.  There's a little bit of literature of psychiatrists as the last shamans of Western medicine.  We don't typically wear the white coats.  We treat the unexplained.  We exist apart.  We may well be witch doctors.  In the US, insurance payments regard "mental health" and "medical" as separate entities.  But I'm wandering a bit.

Well, what about that literature for combination therapy (T3 and T4) vs monotherapy (T4 alone) for hypothyroidism?  Multiple studies and a meta-analysis have proven no benefit for combination therapy over T4 alone.  However, in several studies, patients had a preference for combination therapy that could not be explained by lab results or quality of life measurements.  In Denmark, one study using double-blind crossover methods treated patients with T3/T4 or T4 alone to equivalent TSH levels.  49% of the patients preferred combination therapy compared to 15% who preferred T4 monotherapy, and quality of life measures and depression and anxiety ratings were generally better on combination therapy than on T4 alone.  T4 monotherapy is safer, less likely to result in hyperthyroidism.  But to say there is no support for the alternative is incorrect.

From the evolutionary point of view in general a bit of seaweed and some selenium won't hurt.  In the case of Hashimoto's one must take care with iodine supplementation lest one worsen the condition (this seems less likely to happen if selenium is topped off).  Selenium excess is also a pretty bad idea.

But looking at the more modern basis of hypothyroid and depression treatment, the science behind T4 monotherapy is not yet ironclad.  T3 might yet come back from its banishment to psychiatry.

Friday, February 10, 2012

Thyroid and Psychiatric Illness

The thyroid is one of those glands that is hooked into everything.  Mood, cognition, metabolism, bones, heart, cholesterol… all can be affected by perturbations among the thyroid hormones.

Chris Kresser has done a great series of articles and it's worth a look if you are unfamiliar with the thyroid or if you want a comprehensive refresher.  In fact he did such a good job it seems hardly worth reinventing the wheel, so I thought I would start with psychiatric disease and then address any questions and chase the rabbit holes that will inevitably open up.

My information today comes from a review done for the American Journal of Psychiatry this month and pointed out to me by my fantastic colleague Dr. Hale:  Abnormal Thyroid Function Tests in Psychiatric Patients:  A Red Herring?  This review is conventional to the extreme, but I find it is often very useful to start with conventional reasoning and pick apart where there may be issues or something missing.

I will begin with the briefest of primers so that we are more or less on the same page:

The Killers, All These Things That I've Done (right click to open in new tab)

All right.  As with everything endocrine, there is a feedback loop, but for our purposes we will start with the hypothalamus, which makes a chemical called thyrotropin releasing hormone (TRH).  This chemical toodles on down to the anterior pituitary, which produces thyroid stimulating hormone (TSH).  TSH then directs the thyroid gland itself to release thyroid hormone.  The two major ones are T3 (triiodothyronine) and T4 (thyroxine).  High levels of T3 and T4 should feedback to the pituitary and cause it to decrease the amount of TSH secreted, thus nicely regulating itself.  The other important thing to know is that iodine is essential for the creation of the thyroid hormones, and that T4 is actually a prohormone (and is the major hormone secreted by the thyroid) while T3 is the active hormone.  Selenium is required to turn T4 into T3.

Courtesy Wikipedia Commons
Lots of things can go wrong within this complex system.  For example, a nodule in the thyroid can start producing thyroid hormone like gangbusters and won't respond to feedback inhibition.  This is hyperthyroidism, with classic lab results of high T3, high T4, and typically undetectable TSH.  Symptoms are a racy metabolism, so weight loss, rapid heartbeat, somewhat elevated body temperature, insomnia, anxiety, etc.

In the opposite case, the thyroid can stop responding to the pituitary TSH stimulation and stop producing thyroid hormone.  This is known as hypothyroidism, and will result in low T3 and T4 with a very high TSH.  Symptoms can include weight gain, fatigue, depression, cold intolerance, hair loss, and slow heart rate among others.

These two primary thyroid disorders can cause a host of psychiatric symptoms, including depression, mania, dementia, and even psychosis.   If someone comes to my office with weight gain, cold intolerance, fatigue, and depression, I'd better well check the thyroid and grab a pulse rate while I'm at it.  I'd look pretty silly treating hypothyroidism with therapy or antidepressants.

Besides these basic thyroid problems, thyroid hormones can be off kilter in a variety of other ways.  Chris Kresser's series goes into great detail, but with rare exceptions, these abnormalities are not due to thyroid problems in the actual gland.  Alterations in thyroid function can occur in response to all sorts of systemic illnesses, stress states, and medications, and perturbations in the thyroid function tests not thought to be due to actual hypo or hyperthyroidism is called "nonthyroidal illness." In general, any pattern of tests that don't quite fit the classic  hypo/hyperthyroid patterns will indicate a nonthyroidal illness.

Sepsis, heart attack, major surgery, autoimmune disease… all of these can lead to a characteristic pattern of thyroid tests including low T3, normal to low T4, and high reverse T3.  TSH is often normal, but can be low and later become elevated during recovery.  These abnormalities are extremely common and are seen in about 75% of hospitalized medical patients.  The kicker is these abnormalities seem to be a physiologic response to the illness and they resolve without any intervention in a few months.  The reason these changes happen is (as always) complicated, but inflammatory cytokines such IL-6, IL-1, and TNF alpha are likely involved, altering feedback regulation along the hypothalamic-pituitary-thyroid axis.

Starvation, fasting, or a very low carb diet can tend to lead to low TSH, normal or slightly elevated free T4, and low T3.  There is nothing wrong with the thyroid and this is not "hypothyroidism" per se, but a normal physiologic response to perceived starvation, and it should resolve without other intervention once someone stops fasting or increases carbohydrate intake.  Sepsis (severe infection) will often present with low TSH, normal free T4, and low free T3, a similar pattern.  Again, once the infection is cleared, the abnormalities will resolve on their own.  This "low T3" syndrome is a bad predictor in the case of cardiovascular disease (1), but that doesn't mean that treating with T3 would be smart.  There is some reason to suspect that "low T3" may be a maladaptive response and T3 after a heart attack may be a good idea after all (2), but I think the proof will be in future research (3).

As we noted before, primary thyroid problems can cause psychiatric symptoms.  However, the reverse is also true, and up to 33% of psychiatric inpatients will have abnormal thyroid tests.  As in the case of the medical "nonthyroidal illness," these abnormalities will tend to be characteristic of the disorder and will also resolve on their own within a few months.  In acute psychosis, for example, TSH is usually normal while total T4 is often elevated.  In mania, total T4 and free T4 will be elevated.  In depression, TSH may be a little low or high, with a high free T4 and low or high total T3.

In general, it is recommended that nonthyroidal illness is NOT treated with thyroid hormone.  In nonthyroidal illness, the low T3 or other abnormality may be part of the adaptive inflammatory response (I've linked some thoughts about possible exceptions above).  This reasoning is why conventional medicine suggests testing TSH alone, and checking other hormone levels only if the TSH is out of whack.  Without multiple findings indicative of thyroid problems (a typical hyper or hypothyroid) symptom complex, it is unlikely to be a primary thyroid issue, except in the elderly, who can sometimes show few symptoms.    Other folks with a history or family history of autoimmune disease, treatment with lithium, radiation exposure, goiter, etc. are obviously at higher risk for primary thyroid disease and one should have higher suspicion.

"Subclinical hypothyroidism" is a bit of a gray area between true thyroid illness and the nonthyroidal problems.  TSH will be high, while free T4 will be low or normal. Usually multiple hypothyroid symptoms will indicate a thyroid problem, while no symptoms will indicate nonthyroidal illness and will resolve on its own, which should show up in serial lab tests over months.

From my perspective as a physician, I tend to rely on the TSH and not aggressively pursue mildly abnormal T4s or T3s, particularly if there are no other symptoms.  However, I think low grade iodine and selenium deficiencies are rarely thought of by a conventional physician and may lead to thyroid symptoms and subclinical or confusing lab results. ("Are you eating too much millet? Is not a typical question in the standard medical interview). In addition, there is some controversy as to the appropriate range of TSH considered normal.  In the past it was around 0.8 or 1.0-6.  Now many labs have narrowed the threshold by reducing the upper limit to 3.5 or 4.  However, in most true hyperthyroidism (99%) there will not be much of a question -- TSH will be undetectable.  In true hypothyroidism, it is not unusual to see levels higher than 20.

TSH levels >2.5 are associated with a greater risk of cardiovascular disease.  But is that due to other factors, such as systemic inflammation?  Does it make sense to use thyroid hormone to treat a mere number?  How is that different from treating a cholesterol number with a medicine for the specific purpose of getting the number into a "better" range?  I think we are still coming to a consensus as to the right thing to do in the case of "subclinical hypothyroidism."

As we discussed in the comments of a previous post, psychiatry is pretty much the only specialty where we have a large amount of data and clinical reason for using T3 hormone to treat depression symptoms.  Most primary care doctors and endocrinologists will use T4 exclusively.  In general, T4 the prohormone is safer, and the body should be able to make about as much T3 as it needs (provided selenium levels and vitamin levels are okay).  Conversely, being too aggressive with T3 can lead to death.

However, as I noted, I've found T3 to be generally ineffective or uncomfortable for most, and the only folks who seem to respond well already have diagnosed hypothyroidism and are on synthetic T4.  I've also found that the recommended psychiatry doses (25 to 50 mcg T3) are way too high, and lead to mild hyperthyroidism symptoms within several months.  I've had better luck with lower doses of T3 (around 5 mcg) combined with lowering the dose of T4.  My anecdotes are hardly data, but I think I might have caught some poor converters from T4 to T3, or maybe they are selenium deficient.  In conventional endocrinology these folks don't really exist, but I'm usually able to get away with treatment if I document "for psychiatric indication."

Thursday, February 9, 2012

Upcoming Talks and Topics

Foster the People, Don't Stop (right click to open in new tab)

Time is flying by and my clinic is very busy, and the phone is ringing off the hook, but I did want to take a moment to list the planned upcoming talks and panels for the year (so far):

March 14-18 at PaleoFX12.  I will be on a panel about addressing the psychology of change.  Very excited to have a reason to go down to Austin for a long weekend, as it is my home town and where many of my lifelong friends live.

May 23rd at the Massachusetts Psychiatric Society Geriatric Interest Group meeting in Wellesley, Massachusetts.  I'll be doing a talk for psychiatrists who specialize in treating the elderly on Evolutionary Medicine and Alzheimer's Disease.  I'm thrilled for this opportunity to speak to my peers, as I've trained in conservative institutions, and I have the tendency to believe that any psychiatrist who reads my blog will think I'm a crackpot.  For this reason I'm sure the talk will be squeaky clean with regards to literature references and the best accuracy I can muster, and hopefully exciting and thought-provoking for the attendees.

August 9-12 at the Ancestral Health Symposium 2012 in Cambridge.  I'll be doing a short presentation and will really enjoy seeing all my paleosphere friends again.

I have also been asked about possibly speaking for the Boston-area Paleo Interest group perhaps in the spring but I believe we were going to regroup after holidays/winter, as it is nearly useless making plans when there might be a big snowstorm (ironically the only one we've had was last October, the day before I spoke at Harvard Law School!)

My plan for upcoming blog topics:  Finally, at long last, for real, the Thyroid, with a focus on psychiatric implications.  The first in this series may even come tonight… but more likely tomorrow.

And then I plan to take on that interesting alt med diagnosis known as adrenal fatigue.

I still have stacks of other interesting papers, plus the new ones that come up.  Always more interesting things than I could possibly have time to look into.  And a number of books that need book reviews.  Any tremendously wealthy reader willing to sponsor a year's salary so I can catch up is more than welcome to do so ;-) Of course then I would be spoiled for any future clinical endeavors and lose my usefulness as an active, front-lines interpreter of the literature, so perhaps I'm much better off with the status quo.

Saturday, February 4, 2012

Magnesium Deficiency and Fibromyalgia

Free the Animal's Richard Nikoley may have no use for government (I recommend the depressing but excellent book, Humanity, A Moral History of the 20th Century to get some measure of the amount of systematic human death and suffering caused by government even recently), but I must say I do appreciate the United States of America hosting the organized repository of online knowledge that is PubMed.

I'm old enough to remember hunting the Stacks in the undergraduate library. Even then we had Wargames-era computerized search engines. Half the time you would get sent to something on microfiche and you would give up. In medical school, Medline, MedlinePlus, Ovid, and LoansomeDoc were still ways to search (and you still had to comb the library for the actual paper journal nearly all of the time). In most cases we would do almost anything to avoid a literature search and generally gave presentations straight from textbooks.

Look at me now. Voluntarily doing literature searches for the purposes of gaining knowledge and stuff.

The Ting Tings:  Hang it Up (right click to open in new tab--VEVO so there's an ad the first time through.  Sorry about that, but I think this song is a new, and it is rockin'.)

Now if the whole shebang could be shifted to PubMed Central and free full text were the norm…well.  I suppose my school (I'm not going to mention the name of it, because we all know what happened the last time) would have to find some other way to pay me for my teaching duties than academic journal access. Maybe money of some kind, a discount on malpractice insurance, a holiday basket, a free MRI or something. But for now I get PubMed's friendly My NCBI to email me automatically and regularly with searches of interest. And then I'm able to plug the search results into my school's online academic access for full text so the emails are not a horrible tease.

Sometimes I get a lot of results for boring articles about rats on ketogenic diets, or the latest review in Hungarian about sleep disorders. Sometimes I hit the veritable Evolutionary Psychiatry jackpot, relatively speaking.

It's a small study, 60 women with fibromyalgia. Nothing definitive but certainly very interesting. Have I talked about fibromyalgia before? It's a disease characterized mostly by generalized muscle pains and body aches, fatigue, and poor sleep. Like irritable bowel syndrome, a good proportion of the folks I see in my outpatient clinic that I see for anxiety or depressive disorders have been diagnosed with fibromyalgia. I would say men tend to be more on the irritable bowel side while the afflicted women generally have a nice helping of both, in combination with long term anxiety, depression, and often some autoimmune arthritis or skin issues. Fibromyalgia is one of those debilitating conditions that many doctors (and lay people) consider the 21st century version of hysteria, partially because there are no definitive biomarkers, no x-ray findings, it tends to co-occur with depression and anxiety, and it can respond somewhat to certain antidepressants.

My guess is that fibromyalgia is a variant of depressive disorders that is mediated by a poorly regulated stress response combined with broken sleep, oxidative stress, and inflammation. There's very likely a gut microflora connection. I can further speculate that a program of stress reduction, a nutrient-rich, toxin-avoidant diet, sensible exercise and good sleep hygiene will go a long way to help a large percentage of those with fibromyalgia.

The diagnosis of fibromyalgia has become more popular recently because there is a shiny new Drug to treat it, Cymbalta (duloxetine), which is also FDA-approved for major depressive disorder. There are, of course, no studies as far as I know for paleo diets combined with intensive lifestyle interventions for fibromyalgia, so it is madness and pseudoalternative crap medicine to promote that idea on my blog, whereas there is growing literature evidence for Cymbalta (and pregabalin and milnacipram, the other two FDA-approved treatments). Cymbalta is one of the class of second generation mixed norepinephrine and serotonin-reuptake inhibitors. And I would have to say, in my experience working with people, it really does seem to help the annoying, constant aches of fibromyalgia in many. Cymbalta can also cause weight gain, sedation and a host of other irritating antidepressant side effects, and it is expensive.

Of course, the dirty little secret of expensive pharmaceuticals is that there are older, dirt-cheap antidepressants that are equally effective for fibromyalgia, called tricyclic antidepressants (TCAs).  To be perfectly fair, the TCAs are fatal in overdose and cause much more weight gain, sedation, and deal-breaking dry mouth than the second-generation Cymbalta.

But what if there were an even cheaper, easier, less side-effect laden pill or supplement to take for fibromyalgia? How about magnesium? If you like more detail, go read my Psychology Today article, Magnesium and the Brain: The Original Chill Pill. It combines the information from several articles from this blog. To summarize, magnesium deficiency can cause us to be more vulnerable to a poorly regulated stress response, and magnesium is absolutely necessary to metabolize energy efficiently. Many on a Standard American (or whatever) Diet are likely to be at least somewhat magnesium deficient. Since most magnesium is stored within cells and bones, a simple serum level generally won't tell us much. Since we die rather quickly of heart problems if our blood levels are low, our regulatory systems pull out all the stops to make sure our blood levels remain within a certain range, even if our bodies are relatively deficient.

Back to the study. These researchers took 60 women with fibromyalgia and 20 controls.  The patients were randomized into three groups, magnesium citrate 300mg daily, amitriptyline 10mg daily (a TCA), or Mg Citrate + amitriptyline for eight weeks.  Number of tender points and a "tender point index" were assessed.  Serum and red blood cell levels of magnesium were measured and followed.  In addition, all the participants took standard scale questionnaires measuring depression, anxiety, and fibromyalgia symptoms.  All of these measures were taken before and after treatment.

Why magnesium?  The researchers were intrigued by the idea of fibromyalgia being a disease of oxidative stress, and mineral deficiencies are known to predispose folks to oxidative stress.  Magnesium plays a critical role in the various processed turning the food we eat and our fuel stores into energy used by the cells.  It was postulated that muscle cells could be low in magnesium while the blood levels were maintained with normal limits (to preserve the heart), and this low magnesium could cause problems with muscle cells turning fuel into energy, thus fatigue, weakness, and pain.  A previous study showed that 300-600 mg of magnesium malate daily improved the symptoms of fibromyalgia (1).  Another trial used a mix of magnesium supplements (low and high) with similar results to the previous study in the high-dose arm (2).

In the brand new study, here are the results:

...magnesium levels [both serum and red blood cell] were lower [in fibromyalgia patients] than in the control groups and there was a correlation between magnesium and VAS, the number of tender points, tender point index, the FIQ, the Beck depression and anxiety score and clinical symptoms such as fatigue, sleep disorder, headache, numbness and gastric disorders. All of these findings support the fact that magnesium plays an important role in the development of fibromyalgia.

That's pretty impressive.  And here, then, appears to be the third trial showing clinical improvement with magnesium supplementation for fibromyalgia.  The patients who did best were on a combination of magnesium and amitriptyline (the 10mg dose is quite low and would not expect to have much in the way of antidepressant effects).

Before we get too terribly excited, there are studies showing that sleeping medicines alone will help improve symptoms of fibromyalgia, and one of the most consistent reports of people taking magnesium is that sleep is improved.  Similarly, amitriptyline in a 10 or 25mg dose is often used off-label as a prescription sleep aid.  That might explain the improvement all on its own.

But however the magnesium seems to help, that it does could be significant for many.  It certainly seems worth a try, considering the risks and benefits and costs of the FDA approved treatments (pregabalin, duloxetine, and milnacipram) and the multitude of benefits from getting one's magnesium levels up to snuff.  These are not massive doses.  Considering the average diet gives us maybe 250mg daily, adding 300mg daily puts us just a little above the RDA.  Seems sensible enough to me, anyway.