This lengthy review was published in double spacing format last November. It is now in Endocrine Reviews in a more readable format academic.oup.com/edrv/artic... .
I won't get time to read it soon but I take exception to some of the "ESSENTIAL POINTS".
"A subset of patients do not feel well while taking levothyroxine, despite the best attempts to optimize therapy." I'm not aware of any "best attempts" to optimize therapy. Most attempts are to optimize numbers not signs and symptoms, best attempts would consider the patient.
"trials were largely underpowered" Patients who need T3 have very substantial improvement, often life-changing. The underpowered concept implies that T3 has very little benefit.
A subtext of this and similar papers is the presumption that combination therapy carries greater risk than levothyroxine monotherapy. This is claimed without any observance of the evidence. I've already showed that levothyroxine monotherapy carries an increased cancer risk. Within the next week or so I will put up a post with studies that show levothyroxine monotherapy carries increased cardiac and overall mortality risks. The evidence shows that levothyroxine monotherapy carries much greater risk than combination therapy. Doctors should practice evidence based medicine.
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jimh111
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Yes it does but a large study is only needed if the benefit is minor. If the studies recruited the right patients, and crucially, gave adequate doses of T3 they would get results. By asserting the studies are underpowered she is claiming only a small fraction of patients need T3 and the studies so far gave them enough T3.
It is true that the famous DIO2 polymorphism implies a reduced T4 to T3 conversion. But I tend to think that there are more genes involved (not yet discovered) that could maybe "offset" its impact, such as genes that make the body produce more "carriers" or make the cells receptors more "sensitive" once t3 is lower than before. Could it make sense?The only way to measure Thyroid hormone in tissues is by doing a biopsy, not by T3 or T4 ir TSH.
The polymorphism results in a small reduction of conversion. People are genetically adapted to this but don't adapt the levothyroxine monotherapy so well. I feel the effects of the polymorphism are minor and other factors such as a down regulated axis have far greater effect.
I didn't realise it's the conversion of exogenous LT4 that is mainly impaired by the snp, rather than glandular T4
I have the Dio snp/ homozygous so according to Pannicker et al conversion is further impaired.
No idea how things were with me before replacement T4.
Maybe another reason for testing everyone at a certain point in life ( age?) that would provide a baseline for later comparison when/if thyroid problems developed.
No the polymorphism applies to type-2 deiodinase (D2) of all T4 no matter where it comes from. Levothyroxine places additional demand on D2 leading to minor cognitive difficulties that people who are not homozygous for the polymorphism don't experience.
People with the polymorphism have less D2 activity, they convert less T4 to T3 and so rely more on circulating T3. If they are on levothyroxine monotherapy they are less able to make up for the reduced supply of T3. They would normally get some T3 from the thyroid but having a lower conversion rate they can't get enough from levothyroxine monotherapy.
Forgot to say measuring T3 in tissues would be have limited value, it's more important to measure of thyroid hormone activity. This can be done indirectly by observing signs and symptoms.
The difficult thing is to know for SURE that symptoms are in fact related to Thyroid. Many symptoms, if not all, are completely non specific and could be due to a long list of other conditions. And as we get older, it's even harder to distinguish.
Some signs such as delayed ankle reflexes and dry skin are quite specific to hypothyroidism. It can be difficult to identify some symptoms, it's a matter of seeing if they respond to thyroid hormone without causing hyperthyroid like signs.
These signs and symptoms are far more reliable than TSH, no study has demonstrated a reliable relationship between TSH and symptom severity.
'delayed relaxation phase of ankle reflex' is a well known test that is very specific to hypothyroidism . It was finding this during an examination that prompted my GP to do the TSH /T4 /TPOab tests that led to my diagnosis . When i was overmedicated a few yrs ago , my startle reflex was so fast and extreme it was dangerous to walk up behind me if i was washing up .. in case i had a knife i my hand .
if my dose is increased by too much it results in increased frequency of bowel movements, if dose is then decreased by too much it leads to chronic constipation . increase dose again by just the right amount = normal frequency bowel movements.
Aching in my lower arms and wrists is a reliable early 'tell' for undermedication, it was one of my symptoms at diagnosis, and always resolves very quickly when my medication is correct.
Thyroid hormone dose is pretty easy to monitor by your own specific symptoms once you have got to know what they are...granted this takes years of personal observation, and we are all have different 'signs' , so , mine probably won't work for you , yours probably wont work for the next person.
PULSE PRESSURE...copied from a reply on this forum ,(don't know who wrote it now, sorry)
"an old internist told me pulse pressure was how they used to check for overmedication before blood tests.
Simply take blood pressure and subtract bottom number from top number;
eg. 120/80 ~ 120 -80 =40
Then multiply that answer x pulse rate;
eg. if pulse 60 ~ 60 x 40 = 2400
If the resulting number is around 3200 or higher they used to cut thyroid medication as it was too much. This has been 100% accurate for me.
Through the months i was cutting medication , my number was ranging between 3600-4200.
Now 4 months later, my number is routinely under 2800.
I am very much looking forward to your forthcoming post. Interestingly, my angina was by far the worst of all on Levothyroxine and has completely resolved on NDT.
Thanks. The tradegy is that these doctors genuinely believe they are adopting an evidenced based approach because they are unable to accept that not all patients need normal hormone levels, some of us need abnormal levels of T3 to recover.
Thanks Jim, i've started reading it... and this Hogwarts quote comes to mind :
Sybill Trelawney: My dear, from the first moment you stepped foot in my class... I sensed that you did not possess the proper spirit for the noble art of Divination. No, you see, there. You may be young in years, but your heart is as shriveled... as an old maid's, your soul as dry as the pages of the TSH books ... to which you so desperately cleave. (Hermione pushes a crystal ball on the ground and storms out...)
Thanks. I didn't know you went to Hogwarts, I went to the local school.
Isn´t this the same old message???First of all, the conviction that most patients can be optimally treated with levothyroxine only, and that only a minority of patients need T3. I have never seen any reliable statistics to back up that belief, though. After years of reading posts on various thyroid forums, I have come to suspect that many thyroid patients on levo only have symptoms that they attribute to other things, such as stress, puberty, pregnancy/childbirth, menopause...symptoms that can all be caused or worsened by hypothyroidism (and an undermedicated patient remains hypo). Doctors then put them on antidepressants, anti-anxiety drugs, sleeping pills, statins, sex hormones, blood pressure medication...they never suspect that too little thyroid hormone could be the culprit. So, I think many patients on levo do not feel as fine as doctors think, as many of their symptoms are not seen as having anything to do with their thyroid status.
One problem is that doctors have been brainwashed for years and told that levo is the only safe form of treatment. Doctors who think outside the box and prescribe alternative treatments are often ostracised by their peers and persecuted by the authorities. So it´s not easy swimming against the tide. The doctors who prescribe T3 and other alternative forms of treatment have to go into private practice to do so but, even then, they can be harassed. Think Drs. Peatfield and Skinner. Some give up their licence to become naturopaths.
When you say Within the next week or so I will put up a post with studies that show levothyroxine monotherapy carries increased cardiac and overall mortality risks, are you referring to people on suboptimal doses of levothyroxine, or any dose of levo?
Many patients on levothyroxine do OK, about 85% according to studies. This 85% may not be perfect but have minor issues that don't show up in tests. I've spoken to friends on levothyroxinie and they say they feel fine, perhaps they are not perfect but their problems are nothing compared to what some thyroid patients suffer. On this basis I don't worry about them and have up until now accepted that levothyroxine monotherapy is fine for them.
The post I will put up will list studies that show that a high normal fT4 carries cardiac and overall mortality risks - amongst the general population. Levothyroxine monotherapy generally requires a high normal fT4 to achieve an average fT3 and symptom resolution (for the 85% mentioned above). My post will show that levothyroxine monotherapy is not safe, even if the patients do very well on it. It is safe for patients who do not need their fT4 in the upper half of the reference interval, a small group I suspect. It's not levothyroxine that's the problem, it's the above average fT4 levels that levothyroxine monotherapy requires. More details to follow!
Just the mention of levothyroxine brings back to my mind the simply awful time I and my husband had to go through due to me having very awful palpitations during the night.
Even the cardiologist (I had umpteen overnight recordings) was puzzled and was contemplating putting an implant in my heart to 'see what was going on'. Just then, fortunately I had T3 added to T4 and my body absorbed it and after a little while I stopped T4 and have had no heart problems since then. I have taken T3 alone since.
Goals of Levothyroxine Therapy, Standard of care goals
It's utterly dishonest to show 'Table 1' of symptom improvement from the early days of treatment with NDT when discussing how effective hypothyroidism treatment (with Levo !) can be.
Subclinical hypothyroidism
" One could speculate that these trials could potentially have had different results if the TSH reference interval used was age-adjusted and resulted in a different definition of SCH, with a higher TSH value such as greater than 7 to 10 mIU/L being used for enrollment. "
One could also speculate that if they hadn't undertreated the patients, (TSH 3.6!)_ the original trials could have had different results.
Therapy Other Than Levothyroxine
"It is generally agreed that LT4 is the standard-of-care therapy for hypothyroidism (1). When they are treated to consistently achieve a normal TSH, the majority of patients are believed to feel well while taking LT4, albeit more high quality studies to confirm this would be a valuable addition to our understanding. However, there is a subset of patients who do not feel fully restored to health and report reduced QOL despite being biochemically euthyroid.... "
So she happily accepts that 'generally agreed' view that the majority ARE BELIEVED to feel well on Levo without much question , and then goes on to write 4 massive paragraphs suggesting that surveys reporting Residual Symptoms while Taking Levothyroxine must be treated with suspicion since "The challenge, however, in interpreting these types of studies is that their findings are affected by the health of the control group and the potential that recruitment methods may capture more involvement from individuals concerned about their health or that surveys may elicit a higher response rate from individuals who are dissatisfied."
Make your mind up Jacqueline ! .... either we need to scrutinise the evidence base properly, and pull every scrap to pieces... or we can happily accept that if a few people with a selection bias (endocrinologists/ GP's) 'generally believe' something to be true, it is probably true..Which is it ?
I can only assume Jacqueline has been so busy writing this massive tome of regurgitated propaganda that she hasn't had any time to read any of the recent studies done by more curious and observant researchers.
I could go on , but since i'm only half way through and she's already annoyed me so much, i've decided i'm not going to waste any more of my day reading the rest of it.
Some parts of the latter half of the paper are more encouraging e.g this ~ of the subject of early am pre dose testing for T3 levels:
"Attention to the timing of phlebotomy is particularly important if LT3 is given only once daily. Serum T3 and FT3 levels peak approximately 2.5 hours after dose administration (174, 192, 229, 230). A trough serum T3 level is clearly both lower and more predictable than a postdose T3 level, as illustrated in 3 studies of once-daily LT3 dosing (174, 192, 229). The 24-hour profile of serum TSH concentrations following once-daily LT4/LT3 administration appears to show more fluctuation than serum TSH levels following daily LT4 administration (174). In patients receiving combination therapy, the TSH nadir was at 6 hours following LT4/LT3 dosing, before returning to the predosing value about 10 hours later (174). If a trough T3 concentration, and its associated TSH level, was being targeted because of the predictability of analyte values before the next LT3 dosing, phlebotomy in the early morning before any of that day’s LT3 administration might be particularly useful for monitoring therapy.
Beats me shaws, because the science is out there...and increasing.
This evening...
a quote from an advert aired on television for the OU -"I don't want you to listen to me I want you to listen to the science".
That's it...
"Listen to the science", is crucial
But, when will they ever learn?
There is another thing I am struggling to understand: if supra-physiological levels of T4 cause cancer and cardiac disease among other things, why don´t most Graves´ patient get either cancer or heart disease or both?
it's presumably a long term thing ?.......if people with 'full on' Graves remained untreated they probably would have significantly higher incidence of both, assuming they didn't have a thyroid storm and die of that first..... but these people don't usually remain untreated for years.
I'm sure there's lots of evidence of long term subclinical Hyperthyroidism being associated with higher risks for some kinds of heart failure.
Presumably. But not necessarily. We'll just have to wait until jim reveals all - if he does. I'm afraid he rather let us down with the levo-cancer connection. Eh, jim?
After reading ibshypo.com/index.php/thyro... you need to click on the 'liver cancer and breast cancer' link at the bottom of the page which details how these cancers are an exception and then click on the link at the bottom of that page and so on. Each topic on the website is arranged in chunks of digestible topics so they can be read one at a time or printed off.
Perhaps I should have mentioned at the time Jim ...it took me a while to figure out there was more than one page as it's not immediately obvious... perhaps it needs a 'Next Page' highlight thingy to click on at the bottom of page one ?
i'm possibly not the only one who didn't realise how to get to the next bit .
Did you do what i did at first ...and think it was just the one page ?
There are about 5 pages with lots of studies to consider as evidence for /against, once you figure out how to find them ...... There's a drop down menu thingy in the red box at the top 'Thyroxine (T4) and cancer' or the next page comes up when you click the highlighted text at the end of the page .
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