A Medical Mystery: Thyroid Hormones, Chronic Fatigue and Fibromyalgia

Sum­mary:

  • Chronic Fa­tigue and Fibromyal­gia look very like Hy­pothy­roidism.

  • Thy­roid Pa­tients aren’t happy with ei­ther the di­ag­no­sis or treat­ment of Hy­pothy­roidism.

  • It is pos­si­ble that lots of FMS/​CFS cases are ‘some­thing wrong with the thy­roid sys­tem that doesn’t show up on lab­o­ra­tory hor­mone level tests’.

  • It’s pos­si­ble that it’s not too difficult to fix these CFS/​FMS cases with thy­roid hor­mones.

  • I be­lieve that there may have been a stu­pen­dous cock-up that’s hurt mil­lions.

  • Less Wrong should be in­ter­ested, be­cause it could be a real ex­am­ple of how bad in­fer­ence can cause the sci­ences to come to false con­clu­sions, as well as a good prac­tice prob­lem for the things we re­ally care about.


Edit:

    I found a pos­si­ble an­swer here:
    http://​​less­wrong.com/​​lw/​​nbm/​​thy­roid_hor­mones_chronic_fa­tigue_and_fibromyal­gia/​​
    I do not be­lieve it, be­cause I do not un­der­stand it, but con­tem­pla­tion of it seems to be en­light­en­ing. In par­tic­u­lar, the prob­lem is much broader than I origi­nally thought.

    A sum­mary of the ar­gu­ment in the first two posts, to­gether with links to lots of ev­i­dence in the liter­a­ture:

    http://​​less­wrong.com/​​r/​​dis­cus­sion/​​lw/​​nef/​​the_thy­roid_mad­ness_core_ar­gu­ment_ev­i­dence/​​

    And this is pretty much proof, I think:

    http://​​less­wrong.com/​​lw/​​nhs/​​the_thy­roid_mad­ness_two_ap­par­ently_con­tra­dic­tory/​​

    At this point, I think I’m as con­fi­dent as I can be with­out some sort of for­mal trial (so 25% maybe?)

    But cer­tainly, if you’re suffer­ing from Chronic Fa­tigue Syn­drome/​Fibromyal­gia/​Ma­jor De­pres­sion/​Ir­ri­ta­ble Bowel Syn­drome, or any of the many similar di­s­or­ders which just seem to be differ­ent names for ‘hy­pothy­roidism with nor­mal TSH’, I reckon this is worth try­ing!

    I have done, and it worked for me. For about four months now...


    Origi­nal Post:

    I be­lieve that I’ve come across a gen­uine puz­zle, and I won­der if you can help me solve it. This prob­lem is com­pli­cated, and sub­tle, and has con­founded and defeated good peo­ple for forty years. And yet there are huge and ob­vi­ous clues. No-one seems to have con­ducted the sim­ple ex­per­i­ments which the clues sug­gest, even though many clever peo­ple have thought hard about it, and the an­swer to the prob­lem would be very valuable. And so I won­der what it is that I am miss­ing.

    I am go­ing to tell a story which rather ex­trav­a­gantly priv­ileges a hy­poth­e­sis that I have con­cocted from many differ­ent sources, but a large part of it is from the work of the late Doc­tor John C Lowe, an Amer­i­can chi­ro­prac­tor who claimed that he could cure Fibromyal­gia.

    I my­self am drown­ing in con­fir­ma­tion bias to the point where I doubt my own san­ity. Every time I look for ev­i­dence to dis­con­firm my hy­poth­e­sis, I find only new rea­sons to be­lieve. But I am ut­terly un­qual­ified to judge. Three months ago I didn’t know what an amino acid was. And so I ap­peal to wiser heads for help.

    Crocker’s Rules on this. I sus­pect that I am be­ing the most spec­tac­u­lar fool, but I can’t see why, and I’d like to know.

    Set­ting the Scene

    Chronic Fa­tigue Syn­drome, Myalgic En­cephal­itis, and Fibromyal­gia are ‘new dis­eases’. There is con­sid­er­able dis­pute as to whether they even ex­ist, and if so how to di­ag­nose them. They all seem to have a large num­ber of pos­si­ble symp­toms, and in any given case, these symp­toms may or may not oc­cur with vary­ing sever­ity.

    As far as I can tell, if some­one claims that they’re ‘Tired All The Time’, then a com­pe­tent doc­tor will first of all check that they’re get­ting enough sleep and are not un­duly stressed, then rule out all of the known dis­eases that cause fa­tigue (there are a very lot!), and fi­nally di­ag­nose one of the three ‘by ex­clu­sion’, which means that there doesn’t ap­pear to be any­thing wrong, ex­cept that you’re ill.

    If wide­spread pain is one of the symp­toms, it’s Fibromyal­gia Syn­drome (FMS). If there’s no pain, then it’s CFS or ME. Th­ese may or may not be the same thing, but Myalgic En­cephal­itis is preferred by pa­tients be­cause it’s greek and so sounds like a dis­ease. Un­for­tu­nately Myalgic En­cephal­itis means ‘hurty mus­cles brain in­flam­ma­tion’, and if one had hurty mus­cles, it would be Fibromyal­gia, and if one had brain in­flam­ma­tion, it would be some­thing else en­tirely.

    De­spite the wide­spread be­lief that these are ‘so­matoform’ dis­eases (all in the mind), the sever­ity of them ranges from rel­a­tively mild (tired all the time, can’t think straight), to dev­as­tat­ing (wheelchair bound, can’t leave the house, can’t open one eye be­cause the pain is too great).

    All three seem to have come spon­ta­neously into ex­is­tence in the 1970s, and yet searches for the re­spon­si­ble in­fec­tive agent have proved fruitless. Nei­ther have pal­li­a­tive mea­sures been dis­cov­ered, apart from the tried and true method of tel­ling the suffer­ers that it’s all in their heads.

    The only treat­ments that have proved effec­tive are Cog­ni­tive Be­havi­oural Ther­apy /​ Graded Ex­er­cise. A Cochrane Re­view reck­oned that they do around 15% over placebo in pro­duc­ing a mea­surable alle­vi­a­tion of symp­toms. I’m not very im­pressed. CBT/​GE sound a lot like ‘sports coach­ing’, and I’m pretty sure that if we thought of ‘Not Be­ing Very Good at Row­ing’ as a so­matoform di­s­or­der, then I could pro­duce an im­prove­ment over placebo in a mea­surable out­come in ten per­cent of my vic­tims with­out too much trou­ble.

    But any book on CFS will tell you that the dis­ease was well known to the Vic­to­ri­ans, un­der the name of neuras­the­nia. The hy­poth­e­sis that God lifted the curse of neuras­the­nia from the peo­ple of the Earth as a re­ward for their courage dur­ing the wars of the early twen­tieth cen­tury, while well sup­ported by the clini­cal ev­i­dence, has a low prior prob­a­bil­ity.

    We face there­fore some­thing of a mys­tery, and in the tra­di­tional man­ner of my peo­ple, a mys­tery re­quires a Just-So Story:

    How It Was In The Beginning

    In the dark days of Vic­to­ria, the brilli­ant physi­cian William Miller Ord no­ticed large num­bers of mainly fe­male pa­tients suffer­ing from late-on­set cre­tinism.

    Th­ese pa­tients, ex­hausted, tired, stupid, sad, cold, fat and emo­tional, de­clined steeply, and in­vari­ably died.

    As any man of de­cent cu­ri­os­ity would, Dr Ord cut their corpses apart, and in the midst of the car­nage no­ticed that the thy­roid, a small but­terfly-shaped gland in the throat, was wasted and shrunken.

    One imag­ines that he may have thought to him­self: “What has kil­led them may cure them.”

    After a few false starts and a brilli­ant shot in the dark by the brave Ge­orge Red­mayne Mur­ray, Dr Ord se­cured a sup­ply of an­i­mal thy­roid glands (cheaply available at any butcher, sautée with nut­meg and basil) and fed them to his re­main­ing pa­tients, who were pre­sum­ably by this time too weak to re­sist.

    They re­cov­ered mirac­u­lously, and com­pletely.

    I’m not sure why Dr Ord isn’t bet­ter known, since this ap­pears to have been the first time in recorded his­tory that some­thing a doc­tor did had a pos­i­tive effect.

    Dr Ord’s syn­drome was named Ord’s Thy­roidi­tis, and it is now known to be an au­toim­mune dis­ease where the pa­tient’s own an­ti­bod­ies at­tack and de­stroy the thy­roid gland. In Ord’s thy­roidi­tis, there is no goi­ter.

    A similar dis­ease, where the thy­roid swells to form a dis­figur­ing de­for­mity of the neck (goi­ter), was de­scribed by Hakaru Hashimoto in 1912 (who rather charm­ingly pub­lished in Ger­man), and as part of the war repa­ra­tions of 1946 it was de­cided to con­fuse the two dis­eases un­der the sin­gle name of Hashimoto’s Thy­roidi­tis. Apart from the goi­ter, both con­di­tions share a char­ac­ter­is­tic set of symp­toms, and were eas­ily treated with an­i­mal thy­roid gland, with no com­pli­ca­tions.

    Many years be­fore, in 1835, a fourth physi­cian, Robert James Graves, had de­scribed a differ­ent syn­drome, now known as Graves’ Disease, which has as its char­ac­ter­is­tic symp­toms ir­ri­ta­bil­ity, mus­cle weak­ness, sleep­ing prob­lems, a fast heart­beat, poor tol­er­ance of heat, di­ar­rhoea, and weight loss. Un­for­tu­nately Dr Graves could not think how to cure his epony­mous hor­ror, and so the dis­ease is still named af­ter him.

    The Hor­ror Spreads

    Vic­to­rian medicine be­ing what it was, we can as­sume that an­i­mal glands were sprayed over and into any wealthy per­son un­wise enough to be re­motely ill in the vicinity of a doc­tor. I seem to re­mem­ber a num­ber of jokes about “mon­key glands” in PG Wode­house, and in­deed a man might be tempted to as­sume that chim­panzee parts would be a good sub­sti­tute for hu­mans. Sup­ply is­sues seem to have limited mon­key glands to a few mil­lion­aires wor­ried about im­po­tence, and it may be that the cor­re­spond­ing pro­ce­dure in­flicted on their wives has come down to us as Hor­mone Re­place­ment Ther­apy.

    Cer­tainly any­one look­ing a bit cold, tired, fat, stupid, sad or emo­tional is go­ing to have been eat­ing thy­roids. We can as­sume that in a cer­tain num­ber of cases, this was just the thing, and I think it may also be safe to as­sume that a fair num­ber of peo­ple who had noth­ing wrong with them at all died as a re­sult of treat­ment, al­though the fact that an­i­mal thy­roid is still part of the hu­man food chain sug­gests it can’t be that dan­ger­ous.

    I mean se­ri­ously, these peo­ple use high pres­sure hoses to re­cover the last scraps of meat from the floors of slaugh­ter­houses, they’re not go­ing to care­fully re­move all the nasty gristly throat-bits be­fore they make ready meals, are they?

    The Ar­mour Sausage com­pany, owner of ex­ten­sive meat-pack­ing fa­cil­ities in Chicago, Illinois, and thus in pos­ses­sion of a large num­ber of pig thy­roids which, if not quite sur­plus to re­quire­ments, at the very least faced a mar­ket slug­gish to non-ex­is­tent as food­stuffs, brilli­antly de­cided to sell them in freeze-dried form as a cure for what­ever ails you.

    Some Sort of San­ity Emerges, in a Decade not Noted for its Sanity

    Around the time of the sec­ond world war, doc­tors be­came in­ter­ested in whether their treat­ments ac­tu­ally helped, and an effort was made to de­ter­mine what was go­ing on with thy­roids and the con­stel­la­tion of sad­ness that I will hence­forth call ‘hy­pometabolism’, which is the set of symp­toms as­so­ci­ated with Ord’s thy­roidi­tis. Jump­ing the gun a lit­tle, I shall also define ‘hy­per­me­tabolism’ as the set of symp­toms as­so­ci­ated with Graves’ dis­ease.

    The thy­roid gland ap­peared to be some sort of metabolic reg­u­la­tor, in some ways analo­gous to a ther­mo­stat. In hy­pometabolism, ev­ery sys­tem of the body is run­ning slow, and so it pro­duces a vast range of bad effects, af­fect­ing al­most ev­ery or­gan. Differ­ent suffer­ers can have very differ­ent symp­toms, and so di­ag­no­sis is very difficult.

    Dr Broda Barnes de­cided that the key symp­tom of hy­pometabolism was a low core body tem­per­a­ture. By care­ful ex­per­i­ment he es­tab­lished that in pa­tients with no symp­toms of hy­pometabolism the av­er­age tem­per­a­ture of the armpit on wak­ing was 98 de­grees Fahren­heit (or 36.6 Cel­sius). He be­lieved that tem­per­a­ture vari­a­tion of +/​- 0.2 de­grees Fahren­heit was un­usual enough to merit di­ag­no­sis. He also seems to have be­lieved, in the man­ner of the prover­bial man with a ham­mer, that all hu­man ail­ments with­out ex­cep­tion were caused by hy­pometabolism, and to have given freeze-dried thy­roid to al­most ev­ery­one he came into con­tact with, to see if it helped. A true sci­en­tist. Doc­tor Barnes be­came con­vinced that fully 40% of the pop­u­la­tion of Amer­ica suffered from hy­pometabolism, and recom­mended Ar­mour’s Freeze Dried Pig Thy­roid to cure Amer­ica’s ills.

    In a brilli­ant stroke, Freeze Dried Pig’s Thy­roid was re­named ‘Nat­u­ral Des­ic­cated Thy­roid’, which al­most sounds like the sort of thing you might take in sound mind. I love mar­ket­ing. It’s so clever.

    Amer­ica be­ing in­fested with re­li­gious lu­natics, and Chicago be­ing in­fested with nasty use­less gristly bits of cow’s throat, led al­most in­evitably to a sec­ond form of ‘Nat­u­ral Des­ic­cated Thy­roid’ on the mar­ket.

    Dr Barnes’ hy­pometabolism test never seems to have caught on. There are sev­eral ways your tem­per­a­ture can go out­side his ‘nor­mal’ range, in­clud­ing fever (too hot), star­va­tion (too cold), al­co­hol (too hot), sleep­ing un­der too many du­vets (too hot), sleep­ing un­der too few du­vets (too cold). Also mer­cury ther­mome­ters are a com­plete pain in the neck, and take ten min­utes to get a sen­si­ble read­ing, which is a long time to lie around in bed care­fully do­ing noth­ing so that you don’t in­ad­ver­tently raise your body tem­per­a­ture. To make the situ­a­tion even worse, while men’s tem­per­a­ture is rea­son­ably con­stant, the body tem­per­a­ture of healthy young women goes up and down like the Assyr­ian Em­pire.

    Sev­eral other tests were pro­posed. One of the most in­ter­est­ing is the speed of the Achilles Ten­don Reflex, which is ap­par­ently su­per-fast in hy­per­me­tabolism, and ei­ther weirdly slow or has a freaky pause in it if you’re run­ning a bit cold. Draw­backs of this test in­clude ‘It’s com­pletely sub­jec­tive, give me some­thing with num­bers in it’, and ‘I don’t seem to have one, where am I sup­posed to tap the ham­mer-thing again?’.

    By this time, neuras­the­nia was no longer a thing. In the same way that spiritu­al­ism was no longer a thing, and the Bri­tish Em­pire was no longer a thing.

    As far as we know, Chronic Fa­tigue Syn­drome was not a thing ei­ther, and nei­ther was Fibromyal­gia (which is just Chronic Fa­tigue Syn­drome but it hurts), nor Myalgic En­cephal­itis. There was some­thing called ‘Myalgic Neuras­the­nia’ in 1934, but it seems to have been a painful in­fec­tious dis­ease and they thought it was po­lio.

    Fi­nally, Science

    It turned out that the pur­pose of the thy­roid gland is to make hor­mones which con­trol the metabolism. It takes in the amino acid ty­ro­sine, and it takes in io­dine. It re­leases Thy­roglob­u­lin, mono-iodo-ty­ro­sine (MIT), di-iodo-ty­ro­sine (DIT), thy­rox­ine (T4) and triiodothy­ro­nine (T3) into the blood. The chem­istry is in­ter­est­ing but too com­pli­cated to ex­plain in a just-so story.

    I be­lieve that we cur­rently think that thy­roglob­u­lin, MIT and DIT are sim­ply by-prod­ucts of the pro­cess that makes T3 and T4.

    T3 is the hor­mone. It seems to con­trol the rate of metabolism in all cells. T4 has some­thing of the same effect, but is much less ac­tive, and called a ‘pro­hor­mone’. Its main pur­pose seems to be to be deio­d­i­nated to make more T3. This hap­pens out­side the thy­roid gland, in the other parts of the body (‘periph­eral con­ver­sion’). I be­lieve mainly in the liver, but to some ex­tent in all cells.

    Our fore­fathers knew about thy­rox­ine (T4, or thy­ro­nine-with-four-iodines-at­tached), and triiodothy­ro­nine (T3, or thy­ro­nine-with-three-iodines-at­tached)

    It seems to me that just from the names, thy­rox­ine was the first one to be dis­cov­ered. But I’m not sure about that. You try find­ing a his­tory-of-en­docrinol­ogy web­site. At any rate they seem to have known about T4 and T3 fairly early on.

    The mys­tery of Graves’, Ord’s and Hashimoto’s thy­roid dis­eases was ex­plained.

    Ord’s and Hashimoto’s are dis­eases where the thry­oid gland un­der-pro­duces (hy­pothy­roidism). The metabolism of all cells slows down. As might be ex­pected, this causes a huge num­ber of effects, which seem to man­i­fest differ­ently in differ­ent suffer­ers.

    Graves’ dis­ease is caused by the thy­roid gland over-pro­duc­ing (hy­per­thy­roidism). The metabolism of all cells speeds up. Again, there are a lot of pos­si­ble symp­toms.

    All three are thought to be au­toim­mune dis­eases. Some peo­ple think that they may be differ­ent man­i­fes­ta­tions of the same dis­ease. They are all fairly com­mon.

    Des­ic­cated thry­oid cures hy­pothy­roidism be­cause the ground-up thy­roids con­tain T4 and T3, as well as lots of thy­roglob­u­lin, MIT and DIT, and they are ab­sorbed by the stom­ach. They get into the blood and speed up the metabolism of all cells. By titrat­ing the dose care­fully you can re­store roughly the cor­rect lev­els of the thy­roid hor­mones in all tis­sues, and the pa­tient gets bet­ter. (Ti­tra­tion is where you change some­thing care­fully un­til you get it right)

    The the­ory has con­sid­er­able ex­plana­tory power. It ex­plains cre­tinism, which is caused ei­ther by a ge­netic dis­ease, or by io­dine defi­ciency in child­hood. If you grow up in an io­dine defi­cient area, then your growth is stunted, your brain doesn’t de­velop prop­erly, and your thy­roid gland may be­come hugely en­larged. Pre­sum­ably be­cause the brain is des­per­ately try­ing to get it to pro­duce more thy­roid hor­mones, and it re­sponds by swelling.

    Once upon a time, this swelling (goitre) was called ‘Der­byshire Neck’. I grew up near Der­byshire, and I re­mem­ber an old rhyme: “Der­byshire born, Der­byshire bred, strong in the arm, and weak in the head”. I always thought it was just an in­sult. Maybe not. Cre­tinism was also pop­u­lar in the Alps, and there is a story of an English trav­el­ler in Switzer­land of whom it was re­marked that he would have been quite hand­some if only he had had a goitre. So it must have been very com­mon there.

    But at this point I am *ex­tremely sus­pi­cious*. The thy­roid/​metabolic reg­u­la­tion sys­tem is an­cient (uni­ver­sal in ver­te­brates, I be­lieve), cru­cial to life, and it re­ally shouldn’t just go wrong. We should sus­pect ei­ther an in­fec­tious cause, or a re­cent en­vi­ron­men­tal in­fluence which we haven’t had time to ad­just to, an evolved defence against an in­fec­tious dis­ease, or just pos­si­bly, a re­cently evolved but as yet im­perfect defence against a less re­cent en­vi­ron­men­tal change.

    (Cre­tinism in par­tic­u­lar is very strange. Pre­sum­ably an­i­mals in io­dine-defi­cient ar­eas aren’t cretinous, and yet they should be. Per­haps a change to a farm­ing from a hunter-gath­erer lifestyle has in­creased our de­pen­dency on io­dine from crops, which crops have sucked what lit­tle io­dine oc­curs nat­u­rally out of the soil?)

    It’s also not en­tirely clear to me what the thy­roid sys­tem is *for*. If there’s just a par­tic­u­lar rate that cells are sup­posed to run at, then why do they need a con­trol sig­nal to tell them that? I could be­lieve that it was a literal ther­mo­stat, de­signed to keep the body tem­per­a­ture con­stant at the best speed for the var­i­ous biolog­i­cal re­ac­tions, but it’s uni­ver­sal in *ver­te­brates*. There are plenty of ver­te­brates which don’t keep a con­stant tem­per­a­ture.

    The Fall of Des­ic­cated Thyroid

    There turned out to be some prob­lems with Nat­u­ral Des­ic­cated Thy­roid (NDT).

    Firstly, there were many com­pet­ing brands and types, and even if you stuck to one brand the qual­ity con­trol wasn’t great, so the dose you’d be tak­ing would have been a bit vari­able.

    Se­condly, it’s fuck­ing pig’s thy­roid from an abat­toir. It could have all sorts of nasty things in it. Also, ick.

    Thirdly, it turned out that pigs made quite a lot more T3 in their thy­roids than hu­mans do. It also seems that T3 is bet­ter ab­sorbed by the gut than T4 is, so some­one tak­ing NDT to com­pen­sate for their own un­der­pro­duc­tion will have too much of the ac­tive hor­mone com­pared to the pro­hor­mone. That may not be good news.

    With the dis­cov­ery of ‘periph­eral con­ver­sion’, and the pos­si­bil­ity of cheap clean syn­the­sis, it was de­cided that mod­ern sci­en­tific thy­roid treat­ment would hence­forth be by syn­thetic T4 (thy­rox­ine) alone. The body would make its own T3 from the T4 sup­ply.

    Alarm bells should be ring­ing at this point. Apart from the above points, I’m not aware of any great rea­son for the switch from NDT to thy­rox­ine in the treat­ment of hy­pothy­roidism, but it seems to have been pretty much uni­ver­sal, and it seems to have worked.

    Aware of the lack of T3, doc­tors com­pen­sated by giv­ing peo­ple more T4 than was in their pig-thy­roid doses. And there don’t seem to have been any com­plaints.

    Over the years, NDT seems to have be­come a crazy fringe treat­ment de­spite there not be­ing any ev­i­dence against it. It’s still a le­gal pre­scrip­tion drug, but in Amer­ica it’s only pre­scribed by ec­centrics. In England a doc­tor pre­scribing it would be, at the very least, sum­moned to ex­plain him­self be­fore the GMC.

    How­ever, since it was (a) sold over the counter for so many years, and (b) part of the food chain, it is still perfectly le­gal to sell as a food sup­ple­ment in both coun­tries, as long as you don’t make any med­i­cal claims for it. And the in­ter­net be­ing what it is, the pre­scrip­tion-only syn­thetic hor­mones T3 and T4 are eas­ily ob­tained with­out a pre­scrip­tion. Th­ese are ex­tremely pow­er­ful hor­mones which have an effect on metabolism. If ‘body-builders’ and sports cheats aren’t con­sum­ing all three in vast quan­tities, I am a Dutch­man.

    The Clini­cal Di­ag­no­sis of Hypothyroidism

    We pass now to the be­gin­ning of the 1970s.

    Hy­pothy­roidism is fe­ro­ciously difficult to di­ag­nose. Peo­ple com­plain of ‘Tired All The Time’ well, … all the time, and it has liter­ally hun­dreds of causes.

    And it must be di­ag­nosed cor­rectly! If you miss a case of hy­pothy­roidism, your pa­tient is likely to col­lapse and pos­si­bly die at some point in the medium-term fu­ture. If you di­ag­nose hy­pothy­roidism where it isn’t, you’ll start giv­ing the poor bug­ger pow­er­ful hor­mones which he doesn’t need and *cause* hy­per­me­tabolism.

    The last word in ‘di­ag­no­sis by symp­toms’ was the ab­solutely ex­cel­lent pa­per:

    Statis­ti­cal Meth­ods Ap­plied To The Di­ag­no­sis Of Hypothyroidism

    by W. Z. Billewicz, R. S. Chap­man, J. Crooks, M. E. Day, J. Gos­sage, Sir Ed­ward Wayne, and J. A. Young

    Con­noisseurs will note the clever and care­ful ap­pli­ca­tion of ‘ma­chine learn­ing’ tech­niques, be­fore there were ma­chines to learn!

    One im­por­tant thing to note is that this is a way of sep­a­rat­ing hy­pothy­roid cases from other cases of tired­ness at the point where peo­ple have been referred by their GP to a spe­cial­ist at a hos­pi­tal on sus­pi­cion of hy­pothy­roidism. That changes the statis­tics re­mark­ably. This is *not* a way of di­ag­nos­ing hy­pothy­roidism in the gen­eral pop­u­la­tion. But if some­one’s been to their GP (gen­eral prac­ti­tioner, the doc­tor that a Bri­tish per­son likely makes first con­tact with) and their GP has sus­pected their thry­oid func­tion might be in­ad­e­quate, this test should prob­a­bly still work.

    For in­stance, they con­sider Phys­i­cal Tired­ness, Men­tal Lethargy, Slow Cere­bra­tion, Dry Hair, and Mus­cle Pain, the clas­sic symp­toms of hy­pothy­roidism, pre­sent in most cases, to be in­di­ca­tions *against* the dis­ease.

    That’s be­cause if you didn’t have these things, you likely wouldn’t have got that far. So in the pop­u­la­tion they’re see­ing (of peo­ple whose doc­tor sus­pects they might be hy­pothy­roid), they’re not of great value ei­ther way, but their pres­ence is likely the rea­son why the per­son’s GP has referred them even though they’ve re­ally got iron-defi­ciency anaemia or one of the other causes of fa­tigue.

    In their pop­u­la­tion, the strongest in­di­ca­tors are ‘An­kle Jerk’ and ‘Slow Move­ments’, sub­tle hy­pothy­roid symp­toms which aren’t likely to be pre­sent in peo­ple who are fa­tigued for other rea­sons.

    But this ab­solutely isn’t a test you should use for pop­u­la­tion screen­ing! In the gen­eral pop­u­la­tion, the clas­sic symp­toms are strong in­di­ca­tors of hy­pothy­roidism.

    Prob­a­bil­ity The­ory is weird, huh?

    Luck­ily, there were lab tests for hy­pothy­roidism too, but they were ex­pen­sive, com­pli­cated, an­noy­ing and difficult to in­ter­pret. Billewicz et al used them to cal­ibrate their test, and recom­mend them for the difficult cases where their test doesn’t give a clear an­swer.

    And of course, the fi­nal test is to give them thy­roid treat­ment and see whether they get bet­ter. If you’re not sure, go slow, watch very care­fully and look for hy­per symp­toms.

    Over­con­fi­dence is definitely the way to go. If you don’t di­ag­nose it and it is, that’s catas­tro­phe. If it isn’t, but you di­ag­nose it any­way, then as long as you’re pay­ing at­ten­tion the hy­per symp­toms are easy enough to spot, and you can pull back with lit­tle harm done.

    A Bet­ter Way

    It should be ob­vi­ous from the above that the di­ag­no­sis of hy­pothy­roidism by symp­toms is ab­solutely fraught with com­plex­ity, and very easy to get wrong, and if you get it wrong the bad way, it’s a dis­aster. Doc­tors were ab­solutely scream­ing for a de­ci­sive way to test for hy­pothy­roidism.

    Un­for­tu­nately, test­ing di­rectly for the lev­els of thy­roid hor­mones is very difficult, and the tests of the 1960s weren’t ac­cu­rate enough to be used for di­ag­no­sis.

    The an­swer came from an un­der­stand­ing of how the thy­roid reg­u­la­tory sys­tem works, and the de­vel­op­ment of an ac­cu­rate blood test for a cru­cial sig­nal­ling hor­mone.

    Three struc­tures con­trol the level of thy­roid hor­mones in the blood.

    The thy­roid gland pro­duces the hor­mones and se­cretes them into the blood.

    Its ac­tivity is con­trol­led by the hor­mone thy­rotropin, or Thy­roid Sig­nal­ling Hor­mone (TSH). Lots of TSH works the thy­roid hard. In the ab­sence of TSH the thy­roid re­laxes but doesn’t switch off en­tirely. How­ever the basal level of thy­roid ac­tivity in the ab­sence of TSH is far too low.

    TSH is con­trol­led by the pi­tu­itary gland, a tiny struc­ture at­tached to the brain.

    The pi­tu­itary it­self is con­trol­led, via Thy­roid Re­leas­ing Hor­mone (TRH), by the hy­potha­la­mus, which is part of the brain.

    This was thought to be a clas­sic ex­am­ple of a feed­back con­trol sys­tem.

    hy­potha­la­mus->pi­tu­itary->thyroid

    It turns out that the level of thy­rotropin TSH in the blood is exquisitely sen­si­tive to the lev­els of thy­roid hor­mones in the blood.

    Ad­minister thy­roid hor­mone to a pa­tient and their TSH level will rapidly ad­just down­wards by an eas­ily de­tectable amount.

    So:

    In hy­pothy­roidism, where the thy­roid has failed, the body will be des­per­ately try­ing to pro­duce more thy­roid hor­mones, and the TSH level will be ex­tremely high.

    In Graves’ Disease, this the­ory says, where the thy­roid has grown too large, and the metabolism is run­ning dam­ag­ingly fast, the body will be, like a cen­tral bank try­ing to stim­u­late growth in a defla­tion­ary econ­omy by re­duc­ing in­ter­est rates, ‘push­ing on a piece of string’. TSH will be un­de­tectable.

    The origi­nal TSH test was de­vel­oped in 1965, by the startlingly clever method of ra­dio-im­muno-as­say.

    [For rea­sons that aren’t clear to me, rather than be­ing ex­pressed in grams/​litre, or mols/​litre, the TSH test is ex­pressed in ‘in­ter­na­tional units/​liter’. But I don’t think that that’s im­por­tant]

    A small num­ber of peo­ple in whom there was no sus­pi­cion of thy­roid dis­ease were as­sessed, and the ‘nor­mal range’ of TSH was calcu­lated.

    Again, ‘en­docrinol­ogy his­tory’ re­sources are not easy to find, but the first test was not ter­ribly sen­si­tive, and I think origi­nally hy­per­thy­roidism was thought to re­sult in a com­plete ab­sence of TSH, and that the high­est value con­sid­ered nor­mal was about 4 (milli-in­ter­na­tional-units/​liter).

    This ap­par­ently pretty much solved the prob­lem of di­ag­nos­ing thy­roid di­s­or­ders.

    Forgetfulness

    It’s no longer nec­es­sary to di­ag­nose hypo- and hy­per-thy­roidism by symp­toms. It was er­ror prone any­way, and the ques­tion is eas­ily de­cided by a cheap and sim­ple test.

    Nat­u­ral Des­ic­cated Thy­roid is one with Nin­eveh and Tyre.

    No doc­tor trained since the 1980s knows much about hy­pothy­roid symp­toms.

    Med­i­cal text­books men­tion them only in pass­ing, as an un­weighted list of clas­sic symp­toms. You couldn’t use that for di­ag­no­sis of this fa­mously difficult dis­ease.

    If you sus­pect hy­pothy­roidism, you or­der a TSH test. If the value of TSH is very low, that’s hy­per­thy­roidism. If the value is very high then that’s hy­pothy­roidism. Other­wise you’re ‘eu­thy­roid’ (greek again, good-thy­roid), and your symp­toms are caused by some other prob­lem.

    The treat­ment for hy­per­thy­roidism is to dam­age the thy­roid gland. There are var­i­ous ways. This of­ten re­sults in hy­pothy­roidism. *For rea­sons that are not ter­ribly well un­der­stood*.

    The treat­ment for hy­pothy­roidism is to give the pa­tient suffi­cient thy­rox­ine (T4) to cause TSH lev­els to come back into their nor­mal range.

    The con­di­tions hy­per­thy­roidism and hy­pothy­roidism are now *defined* by TSH lev­els.

    Hy­pothy­roidism, in par­tic­u­lar, a fairly com­mon dis­ease, is con­sid­ered to be such a solved prob­lem that it’s usu­ally treated by the GP, with­out in­volv­ing any kind of spe­cial­ist.

    Pre­sent Day

    It was found that the tra­di­tional amount of thy­rox­ine (T4) ad­ministered to cure hy­pothy­roid pa­tients, was in fact too high. The amount of T4 that had always been used to re­place the hor­mones that had once been pro­duced by a thy­roid gland now dead, de­stroyed, or sur­gi­cally re­moved ap­peared now to be too much. That amount causes sup­pres­sion of TSH to be­low its nor­mal range. The brain, the­ory says, is ask­ing for the level to be re­duced.

    The amount of T4 ad­ministered in such cases (there are many) has been re­duced by a fac­tor of around two, to the level where it pro­duces ‘nor­mal’ TSH lev­els in the blood. Treat­ment is now titrated to pro­duce the nor­mal lev­els of TSH.

    TSH tests have im­proved enor­mously since their in­tro­duc­tion, and are on their third or fourth gen­er­a­tion. The ac­cu­racy of mea­sure­ment is very good in­deed.

    It’s now pos­si­ble to de­tect the tiny re­main­ing lev­els of TSH in overtly hy­per­thy­roid pa­tients, so hy­per­thy­roidism is also now defined by the TSH test.

    In England, the nor­mal range is 0.35 to 5.5. This is con­sid­ered to be the defi­ni­tion of ‘eu­thy­roidism’. If your lev­els are nor­mal, you’re fine.

    If you have hy­pothy­roid symp­toms but a nor­mal TSH level, then your symp­toms are caused by some­thing else. Look for Anaemia, look for Lyme Disease. There are hun­dreds of other pos­si­ble causes. Once you rule out all the other causes, then it’s the mys­te­ri­ous CFS/​FMS/​ME, for which there is no cause and no treat­ment.

    If your doc­tor is very good, very care­ful and very para­noid, he might or­der tests of the lev­els of T4 and T3 di­rectly. But ac­tu­ally the di­rect T4 and T3 tests, al­though much more ac­cu­rate than they were in the 1960s, are quite badly stan­dard­ised, and there’s con­sid­er­able con­tro­versy about what they ac­tu­ally mea­sure. Differ­ent as­say tech­niques can pro­duce quite differ­ent read­ings. They’re ex­pen­sive. It’s fairly com­mon, and on the face of it perfectly rea­son­able, for a lab to re­fuse to con­duct the T3 and T4 tests if the TSH level is nor­mal.

    It’s been dis­cov­ered that quite small in­creases in TSH ac­tu­ally pre­dict hy­pothy­roidism. Minute changes in thy­roid hor­mone lev­els, which don’t pro­duce symp­toms, cause de­tectable changes in the TSH lev­els. Nor­mal, but slightly high val­ues of TSH, es­pe­cially in com­bi­na­tion with the pres­ence of thy­roid re­lated an­ti­bod­ies (there are sev­eral types), in­di­cate a slight risk of one day de­vel­op­ing hy­pothy­roidism.

    There’s quite a lot of con­tro­versy about what the nor­mal range for TSH ac­tu­ally is. Many doc­tors con­sider that the op­ti­mal range is 1-2, and tar­get that range when ad­minis­ter­ing thy­rox­ine. Many think that just get­ting the value in the nor­mal range is good enough. None of this is prop­erly un­der­stood, to un­der­state the case rather dra­mat­i­cally.

    There are new cat­e­gories, ‘sub-clini­cal hy­pothy­roidism’ and ‘sub-clini­cal hy­per­thy­roidism’, which are defined by ab­nor­mal TSH tests in the ab­sence of symp­toms. There is con­sid­er­able con­tro­versy over whether it is a good idea to treat these, in or­der to pre­vent sub­tle hor­monal im­bal­ances which may cause difficult-to-de­tect long term prob­lems.

    Every­one is a lit­tle con­cerned about ac­ci­den­tally over-treat­ing peo­ple, (re­mem­ber that hy­per­thy­roidism is now defined by TSH<0.35).

    Hyper­thy­roidism has long been as­so­ci­ated with Atrial Fibrilla­tion (a heart prob­lem), and Os­teo­poro­sis, both very nasty things. A large pop­u­la­tion study in Den­mark re­cently re­vealed that there is a greater in­ci­dence of Atrial Fibrilla­tion in sub-clini­cal hy­per­thy­roidism, and that hy­pothy­roidism ac­tu­ally has a ‘pro­tec­tive effect’ against Atrial Fibrilla­tion.

    It’s known that TSH has a cir­ca­dian rhythm, higher in the early morn­ing, lower at night. This makes the test rather noisy, as your TSH level can be dou­bled or halved de­pend­ing on what time of day you have the blood drawn.

    But the big prob­lems of the 1960s and 1970s are com­pletely solved. We are just tidy­ing up the de­tails.

    Doubt

    Many hy­pothy­roid pa­tients com­plain that they suffer from ‘Tired All The Time’, and have some of the clas­sic hy­pothy­roid symp­toms, even though their TSH lev­els have been care­fully ad­justed to be in the nor­mal range.

    I’ve no idea how many, but opinions range from ‘the great ma­jor­ity of pa­tients are perfectly happy’ to ‘around half of hy­pothy­roid suffer­ers have hy­pothy­roid symp­toms even though they’re be­ing treated’.

    The in­ter­net is black with peo­ple com­plain­ing about it, and there are many books and al­ter­na­tive medicine prac­ti­tion­ers try­ing to cure them, or pos­si­bly try­ing to ex­tract as much money as pos­si­ble from peo­ple in des­per­ate need of re­lief from an un­pleas­ant, de­bil­i­tat­ing and in­ex­pli­ca­ble malaise.

    THE PLURAL OF ANECDOTE IS DATA.

    Not good data, to be sure. But if ten peo­ple men­tion to you in pass­ing that the sun is shin­ing, you are a damned fool if you think you know noth­ing about the weather.

    It’s known that TSH ranges aren’t ‘nor­mally dis­tributed’ (in the sense of Gauss/​the bell curve dis­tri­bu­tion) in the healthy pop­u­la­tion.

    If you log-trans­form them, they do look a bit more nor­mal.

    The Amer­i­can Academy of Clini­cal Bio­chemists, in 2003, de­cided to set­tle the ques­tion once and for all. They care­fully screened out any­one with even the slight­est sign that there might be any­thing wrong with their thy­roid at all, and mea­sured their TSH very ac­cu­rately.

    In their re­port, they said (this is a di­rect quote):

    In the fu­ture, it is likely that the up­per limit of the serum TSH eu­thy­roid refer­ence range will be re­duced to 2.5 mIU/​L be­cause >95% of rigor­ously screened nor­mal eu­thy­roid vol­un­teers have serum TSH val­ues be­tween 0.4 and 2.5 mIU/​L.

    Many other stud­ies dis­agree, and pro­pose wider ranges for nor­mal TSH.

    But if the AACB re­port were taken se­ri­ously, it would lead to di­ag­no­sis of hy­pothy­roidism in vast num­bers of peo­ple who are perfectly healthy! In fact the lev­els of noise in the test would put peo­ple whose thy­roid sys­tems are perfectly nor­mal in dan­ger of be­ing di­ag­nosed and in­ap­pro­pri­ately treated.

    For fairly ob­vi­ous rea­sons, bio­chemists have been ex­tremely, and quite prop­erly, re­luc­tant to take the re­port of their own pro­fes­sional body se­ri­ously. And yet it is hard to see where the AACB have gone wrong in their re­port.

    Neuras­the­nia is back.

    A lit­tle af­ter the time of the in­tro­duc­tion of the TSH test, new forms of ‘Tired All The Time’ were dis­cov­ered.

    As I said, CFS and ME are just two names for the same thing. Fibromyal­gia Syn­drome (FMS) is much worse, since it is CFS with con­stant pain, for which there is no known cause and from which there is no re­lief. Most drugs make it worse.

    But if you com­bine the three things (CFS/​ME/​FMS), then you get a sin­gle dis­ease, which has a large num­ber of very non-spe­cific symp­toms.

    Th­ese symp­toms are the clas­sic symp­toms of ‘hy­pometabolism’. Any doc­tor who has a pa­tient who has CFS/​ME/​FMS and hasn’t tested their thy­roid func­tion is *de facto* in­com­pe­tent. I think the vast ma­jor­ity of med­i­cal peo­ple would agree with this state­ment.

    And yet, when you test the TSH lev­els in CFS/​ME/​FMS suffer­ers, they are perfectly nor­mal.

    All three/​two/​one are ap­pal­ling, crip­pling, ter­rible syn­dromes which ruin peo­ple’s lives. They are fairly com­mon. You al­most cer­tainly know one or two suffer­ers. The suffer­ing is made worse by the fact that most peo­ple be­lieve that they’re psy­cho­so­matic, which is a po­lite word for ‘imag­i­nary’.

    And the peo­ple suffer­ing are mainly mid­dle-aged women. Mid­dle-aged women are easy to ig­nore. Espe­cially stupid mid­dle-aged women who are wor­ried about be­ing over­weight and ob­vi­ously fak­ing their symp­toms in or­der to get drugs which are pop­u­larly be­lieved to in­duce weight loss. It’s clearly their hor­mones. Or they’re try­ing to scrounge up welfare benefits. Or they’re try­ing to claim in­surance. Even though there’s noth­ing wrong with them and you’ve checked so care­fully for ev­ery­thing that it could pos­si­bly be.

    But it’s not all mid­dle aged women. Th­ese dis­eases af­fect men, and the young. Some­times they af­fect lit­tle chil­dren. Ex­haus­tion, stu­pidity, con­stant pain. End­less other prob­lems as your body rots away. Lifelong. No re­mis­sion and no cure.

    And I have Doubts of my Own

    And I can’t be­lieve that care­ful, nu­mer­ate Billewicz and his co-au­thors would have made this mis­take, but I can’t find where the doc­tors of the 1970s checked for the sen­si­tivity of the TSH test.

    Speci­fic­ity, yes. They tested a lot of peo­ple who hadn’t got any sign of hy­pothy­roidism for TSH lev­els. If you’re well, then your TSH level will be in a nar­row range, which may be 0-6, or it may be 1-2. Opinions are weirdly di­vided on this point in a hard to ex­plain way.

    But Sen­si­tivity? Where’s the bit where they checked for the other arm of the con­di­tional?

    The bit where they show that no-one who’s suffer­ing from hy­pometabolism, and who gets well when you give them Des­ic­cated Thy­roid, had, on first con­tact, TSH lev­els out­side the nor­mal range.

    If you’re try­ing to prove A ⇔ B, you can’t just prove A ⇒ B and call it a day. You couldn’t get that past an A-level maths stu­dent. And cer­tainly any­one with a sci­ence de­gree wouldn’t make that er­ror. Surely? I mean you shouldn’t be able to get that past any­one who can rea­son their way out of a pa­per bag.

    I’m go­ing to say this a third time, be­cause I think it’s im­por­tant and maybe it’s not ob­vi­ous to ev­ery­one.

    If you’re try­ing to prove that two things are the same thing, then prov­ing that the first one is always the sec­ond one is not good enough.

    IF YOU KNOW THAT THE KING OF FRANCE IS ALWAYS FRENCH, YOU DO *NOT* KNOW THAT ANYONE WHO IS FRENCH IS KING OF FRANCE.

    It’s pos­si­ble, of course, that I’ve missed this bit. As I say, ‘His­tory of En­docrinol­ogy’ is not one of those pop­u­lar, fash­ion­able sub­jects that you can eas­ily find out about.

    I won­der if they just as­sumed that the thy­roid sys­tem was a ther­mo­stat. The anal­ogy is still com­mon to­day.

    But it doesn’t look like a ther­mo­stat to me. The thy­roid sys­tem with its vast num­bers of hor­mones and trans­form­ing en­zymes is in­sanely, in­com­pre­hen­si­bly com­pli­cated. And very poorly un­der­stood. And evolu­tion­ar­ily an­cient. It looks as though origi­nally it was the sys­tem that co­or­di­nated meta­mor­pho­sis. Or maybe it sig­nalled when re­sources were high enough to un­dergo meta­mor­pho­sis. But what­ever it did origi­nally in our most an­cient an­ces­tors, it looks as though the blind watch­maker has lay­ered hack af­ter hack af­ter hack on top of it on the way to us.

    Only the thy­roid origi­nally, con­trol­ling ma­jor changes in body plan in tiny crea­tures that meta­mor­phose.

    Of course, hu­mans meta­mor­phose too, but it’s all in the womb, and who mea­sures thy­roid lev­els in the un­born when they still look like tiny fish?

    And of course, hu­mans un­dergo very rapid growth and change af­ter we are born. Espe­cially in the brain. Baby horses can walk sec­onds af­ter they’re born. Baby hu­mans take months to learn to crawl. I won­der if that’s got any­thing to do with cre­tinism.

    And I’m told that baby hu­mans have very high hor­mone lev­els. I won­der why they need to be so hot? If it’s a ther­mo­stat, I mean.

    But then on top of the thy­roid, the pi­tu­itary. I won­der what that adds to the sys­tem? If the thy­roid’s just a ther­mo­stat, or just a de­vice for keep­ing T4 lev­els con­stant, why can’t it just do the sens­ing it­self?

    What evolu­tion­ary pro­cess cre­ated the pi­tu­itary con­trol over the thy­roid? Is that the ther­mo­stat bit?

    And then the hy­potha­la­mus, con­trol­ling the pi­tu­itary. Why? Why would the brain need to set the tem­per­a­ture when the ideal tem­per­a­ture of metabolic re­ac­tions is always 37C in ev­ery an­i­mal? That’s the tem­per­a­ture ev­ery­thing’s de­signed for. Why would you dial it up or down, to a place where the chem­i­cal re­ac­tions that you are don’t work prop­erly?

    I can think of rea­sons why. Per­haps you’re hi­ber­nat­ing. Many of our an­ces­tors must have hi­ber­nated. Maybe it’s a good idea to slow the metabolism some­times. Per­haps to con­serve your fat sup­plies. Your stored food.

    Per­haps it’s a good idea to slow the metabolism in times of famine?

    Per­haps the whole calories in/​calories out thing is wrong, and peo­ple whose en­ergy ex­pen­di­ture goes over their calorie in­take have slow metabolisms, slowly sac­ri­fic­ing ev­ery bod­ily func­tion in­clud­ing im­mune defence in or­der to avoid star­va­tion.

    I won­der at the willpower that could keep an an­i­mal sane in that state. While its body does ev­ery­thing it can to keep its pre­cious fat re­serves high so that it can get through the famine.

    And then I re­mem­ber about Anorexia Ner­vosa, where young women who want to lose weight starve them­selves to the point where they no longer feel hun­gry at all. Another mys­te­ri­ous psy­cholog­i­cal dis­ease that’s just put down to crazy fe­males. We re­ally need some fe­male doc­tors.

    And I re­mem­ber about Seth Robert’s Shangri-La Diet, that I tried, to see if it worked, some years ago, just be­cause it was so weird, where by eat­ing strange things, like taste­less oil and raw sugar, you can make your ap­petite dis­ap­pear, and lose weight. It seemed to work pretty well, to my sur­prise. Seth came up with it while think­ing about rats. And ap­par­ently it works on rats too. I won­der why it hasn’t caught on.

    It seems, my fe­male friends tell me, that a lot of diets work well for a bit, but then af­ter a few weeks the effect just stops. If we think of a par­tic­u­lar diet as a meme, this would seem to be its in­fec­tious pe­riod, where the host en­thu­si­as­ti­cally spreads the idea.

    And I won­der about the role of the thy­ro­nine de-io­d­i­nat­ing en­zymes, and the whole fan­tas­ti­cally com­pli­cated pro­cess of strip­ping the iodines and the amino acid bits from thy­rox­ine in var­i­ous pat­terns that no-one un­der­stands, and what could be go­ing on there if the thy­roid sys­tem were just a sim­ple ther­mo­stat.

    And I won­der about re­ports I am read­ing where elite ath­letes are find­ing them­selves suffer­ing from hy­pothy­roidism in num­bers far too large to be cred­ible, if it wasn’t, say, a phys­i­cal re­sponse to calorie in­take less than calorie out­put.

    I’ve been look­ing ever so hard to find out why the TSH test, or any of the var­i­ous available thy­roid blood tests are a good way to as­sess the func­tion of this fan­tas­ti­cally com­pli­cated and very poorly un­der­stood sys­tem.

    But ev­ery time I look, I just come up with more rea­sons to be­lieve that they don’t tell you very much at all.

    The Mystery

    Can any­one con­vince me that the con­verse arm has been care­fully checked?

    That ev­ery­one who’s suffer­ing from hy­pometabolism, and who gets well when you give them Des­ic­cated Thy­roid, has, be­fore you fix them, TSH lev­els out­side the nor­mal range.

    In other words, that we haven’t just thrown, though care­less­ness, a long stand­ing, perfectly safe, well tested treat­ment, for a hor­rible dis­abling dis­ease that of­ten causes ex­cru­ci­at­ing pain, that the Vic­to­ri­ans knew how to cure, and that the peo­ple of the 1950s and 60s rou­tinely cured, away.