2014 ATA thyroid therapy guidelines: 1. Levothyroxine

American Thyroid Association-LevoIn this series of posts, I paraphrase a 2014 thyroid therapy guidelines document in a way that even the brain-fogged hypothyroid patient can understand more quickly and easily than reading the original version.

Posts in this series:

MY SUMMARY’S AIMS AND METHODS

Every thyroid patient should understand the basics about what is being said about their therapy by the American Thyroid Association (ATA), even if they live in Canada or another country.

These people’s guidelines are cited in other guidelines all over the world today. They have high status among endocrinologists, so they seem to be the ones who ultimately write the rules that overrule our well being. The ATA guidelines are attractive to leaders because they simplify thyroid therapy and make it seem so easy for general practitioners to manage. They are also attractive guidelines because they help physicians to deflect thyroid patients’ symptom complaints and requests for T3 or desiccated thyroid therapy.

I’m attempting to translate their reasoning into conversational discourse. I’ve decided to use everyday question and answer format, and I’ve written their answers using “we” as if they, the guideline writers, are speaking to you directly. 

Anything outside of “quotation marks” is my paraphrase and also includes my interpretations of their attitude toward the subjects they cover.

Wherever I’ve interpreted, I’ve used my broad reading in thyroid science journals including ATA’s main journal called “Thyroid,” my understanding of other guideline documents written by the ATA (such as the 2012 guidelines by the ATA and AACE) and other articles written by some of those who served on this ATA committee.

If you doubt my paraphrases are fair, please go to the original article and read the section number. You can decide whether I have misinterpreted their attitude and/or their stance.

Overall, notice the order and priority of questions. I’m giving the summary in the order they present it.  The questions they start with are not about goals of all thyroid therapy, but rather about the correct use and defense of “levothyroxine” alone.

PARAPHRASE BEGINS

Q: Who wrote these guidelines, how, and why?

A: In 2014, the American Thyroid Association gathered a task force on thyroid hormone replacement because of concerns that some patients “feel unwell while taking levothyroxine monotherapy.”

We eleven co-authors went through a process of identifying 24 questions, reviewing literature, consulting a bioethicist, following processes that were supposed to be designed to minimize bias. We even gained “stakeholder input” at a national meeting. In the end, we achieved consensus on all points.

We’re clearly very proud of our process and we put this first because we want you to put full confidence in our good intentions to address the concerns of patients.

Q1a. Do we think levothyroxine monotherapy should be the standard of care for all primary hypothyroidism?

A: Yes, because the body metabolizes T4 hormone, because it resolves the symptoms of hypothyroidism, has long term benefits, few side effects, is easy to take, can be absorbed easily, has a long half-life in the body, and it’s cheap.

Q1b. What are our goals for levothyroxine replacement in primary hypothyroidism?

A: Our goals are: 1. To resolve all hypothyroid symptoms and signs, 2. to normalize TSH and improve T3 and T4 concentrations from their pre-therapy levels, and 3. to avoid overdose (thyrotoxicosis) especially in the elderly.

However, by the end of this section you will see that we have lowered the priority of goal #1 to the bottom of the list. It’s mainly because we think the data on symptoms is very confusing and we lack good scientific studies on the topic.

In other words, we have to admit that the scientific record shows neglect of this topic of symptom resolution.

Therefore, even though goal #1 sounds great, we absolve ourselves of trying to achieve this goal at this time. We have to wait for science to catch up someday.

In general, it is very hard for us to believe genuine symptoms and signs of hypothyroidism can possibly exist while goal #2 is being achieved.

Therefore, we think goal 2 is what physicians should attend to. It will likely achieve goal #1 anyway in most patients.

Goal #2 is way more about normalizing TSH and supplying T4 than about optimizing your T3. We imply that TSH is more important than T4, and T4 is way more important than T3.

Goal #3 is primarily about preventing TSH from being suppressed. TSH must not be suppressed. Ever. Why? Because we presume that low or suppressed TSH is synonymous with thyrotoxicosis. And because of many low-TSH statistical risk association studies showing a link between low TSH and disorders like osteoporosis and heart problems.

(As for #3, We wanted to scare doctors away from permitting a low TSH, so of course we didn’t emphasize the fact that correlation studies cannot establish causation. They can’t prove that low TSH causes health problems in the absence of elevated FT3 and FT4 and other signs and symptoms of genuine thyrotoxicosis.)

(We also avoided suggesting that having a high T3 alongside a high-normal T4 may cause these health problems instead of a low TSH. That’s because the vast majority of these studies have largely ignored the study of these patients’ FT3 levels, focusing only on TSH or on TSH and FT4 in the absence of any FT3 data).

Q1c-d Are other hypothyroid symptoms and signs beyond TSH, T3 and T4 tests relevant to the effectiveness and dosing of levothyroxine?

A: No. Because these symptoms can be caused by other health factors, we declare that they probably are. 

We have not cared enough to do studies on your symptoms because we believe all valid symptoms have to point to a non-normalized TSH or an insufficient T4 dose or else they are not really thyroid hormone symptoms.

Q2 Which levothyroxine product is better than the other?

A: We want you to stay loyal to brand names of levothyroxine.

Don’t be lured to generic alternatives that are declared to be bioequivalent. Don’t switch between brands because it can change your thyroid hormone levels. It really does not matter if you take this medicine as a tablet or a gel capsule.

(We won’t mention that many of us are still feeling sore about the FDA’s decision, about 15 years ago, to permit generic levothyroxine meds to take up some of the market share of our favorite brand names of levothyroxine. We won’t mention that one of the reasons we don’t put faith in bioequivalence studies is because the FDA refused to make our favorite biomarker, TSH, the main determinant of “therapeutic equivalence” and instead went down the road of simple “bioequivalence,” focusing on the concentration of the main medicinal ingredient, T4 hormone, in blood, after a huge dose of LT4 in healthy-thyroid subjects. To reassert the dominance of TSH over therapy, we at the ATA have made our stance clear in prior publications that TSH — but not necessarily FT4 or FT3 — should be tested after switching between name brand and generic).

Q3 How can you improve levothyroxine absorption and metabolism?

A: To be well on levothyroxine, you have to be aware of many factors that limit levothyroxine effectiveness. Your symptoms may be a result of your own failure to absorb this medication properly and/or metabolize it to enough T3 hormone.

For example, you must take your levothyroxine 60 minutes before breakfast or at least 3 hours after your last meal of the day, and at least 4 hours away from calcium and iron. Certain GI conditions like gastritis and celiac disease will interfere.

In addition, ineffectiveness of this medication may be blamed on a wide variety of supplements and medications, like estrogen and stomach-acid-lowering medications, that can interfere with either its absorption or its metabolism to the active hormone T3.

(Overall, we tend to think that LT4 absorption is more of an issue than LT4 metabolism, given our emphasis on absorption. There are so many other health factors that can take the blame instead of levothyroxine, including your incorrect dosing behavior. To blame poor metabolism, you’d have to eliminate all the possible causes of absorption interference first.)

Q4 How do we adjust your levothyroxine dosage?

A: By TSH alone, of course. Low TSH always means too much levothyroxine and high TSH always means too little.

We consider various factors when we estimate the dose you’ll need to normalize your TSH, such as your weight, your age, pregnancy, thyroid gland status, and presence of heart disease. If any of these factors change, we simply test your TSH again and adjust your dose as needed to normalize your TSH.

Q5 What can we do if levothyroxine interferes with other health conditions?

A: If you’re allergic, use a different L-T4 brand. If your iron is low, raise it.  If you have a cardiac condition, you may need to suffer on a lower dose or take beta-blockers with your levothyroxine. If you have mental health problems while your TSH is normal, get treated separately for that, because that’s a separate medical condition. 

Q6 How do we manage your levothyroxine if you are old, pregnant, or don’t take your meds properly?

A: If you are older, you will get lower doses to start with because we’re afraid of overtreating you. 

We believe you’re going to be just fine if your TSH is mildly above reference range because it’s so common in untreated old people to have a higher TSH when they are untreated. We suggest your TSH could imitate the old population without causing any health problems, even though we can cite no clinical trial evidence to prove that a mildly high TSH causes no harm in a population of old people without any thyroid function.

If you’re pregnant, to protect your fetus, we’ll keep your TSH to trimester-specific reference ranges, we test you as frequently as every month, and we may ask you to take a double dose once a week. Generally, we believe more T4 is always better than less T4 during pregnancy.

If you are an infant born hypothyroid, we will maintain your T4 in the upper half of reference and your TSH in the lower half of reference and we test you every 1-2 months for the first year.

During your life, if your TSH is elevated because we suspect you are forgetting to take your doses, we will protect you by making you take one big dose once a week.

(As you can see, we have a very strong belief in imitating the normal population’s TSH under all circumstances, whether you’re old, pregnant, or an infant. It does not matter to us that dosing levothyroxine without thyroid function will make your T3 is lower than people, as we explain in the next section. All that matters is that you can achieve the same TSH levels as other people in your sex, age, and pregnancy category.)

Q7a-c What do we think of your T3 hormone levels while on levothyroxine?

A: We have no recommendation to make on any of these three questions related to T3, just summary statements and a discussion of some literature.

Overall, we haven’t done enough research to say whether a certain T3 level anywhere within reference or even below reference is bad for you.

(Notice that we’re clearly not that interested in investigating any health outcomes correlated with changes in T3 levels, becasue our eyes are fixed on TSH.)

It’s a biological fact that everyone converts T4 to T3, and the TSH proves that your pituitary gland is getting enough T3. If you have hypothyroid symptoms, we believe your TSH will be high. Therefore, we haven’t worried enough about this issue of T3 levels to study the relationship between your T3 levels and your symptoms or overall health.

We think that dosing T3 is not good for you because it makes your T3 levels fluctuate more than they would in a normal person.

(Notice that we express a fear without evidence. We cite no scientific proof that those T3 fluctuations cause harm. We don’t want to cite the publications that have studied T3 dosing and point out that they mentioned no harm from T3 fluctuations.)

We don’t trust the T3 and Free T3 immunoassay tests we’ve developed. We know they are not as reliable at the lower end of the reference range, so we think we are justified in dismissing them altogether. We’re not interested in developing or refining the testing technology further because the TSH test measures pituitary T3 levels, and that indirect measurement of one tissue’s local T3 supply is good enough for us. In the future, we may choose to use the much more expensive yet accurate LC/MS/MS (mass spectrometry) technique for testing in rare circumstances and research (We won’t talk about who would profit from promoting mass spectrometry Free T3 testing and why we would limit it to rare circumstances).

If your T3 is at the bottom of reference or lower and your TSH is normal, you are probably just sick, or you’re just old, or you’re taking a medicine that depressed your T3 levels, so basically you can’t blame the levothyroxine or its dosage on your lower T3.

We know that having a high T4 level can cause you to lose conversion of T4 to T3, and we know that levothyroxine causes a high T4:T3 ratio in blood (We don’t like calling it a “low T3:T4 ratio” because saying “high” sounds good and “low” makes it sound bad). However, we simply haven’t bothered to study the harms of this T4/T3 imbalance very carefully given that your T4 is in reference range, and we haven’t bothered to notice any significant health problems with this imbalance as long as your TSH is normal (because, as mentioned above, a normal TSH by definition means your health problems are not thyroid hormone related).

We and our preferred pharmaceutical levothyroxine can’t be held responsible for the way certain organs or tissues might become T3-deficient. We know that your body will have different T3 levels in every organ, but that’s up to the organ or tissue to decide in its wisdom.

If some tissues need more T3 because you have a genetic condition like receptor-level “resistance to thyroid hormone” in some tissues, but we’re not going to test you for that. We’d much rather have many parts of your body suffer a T3 deficit than have any single part of it, especially the heart, have too much T3.

Q7d If you are obese, depressed, have high cholesterol, or have no thyroid, do we help you achieve a higher T3 level or lower TSH level?

A: Absolutely not. We believe that people who have no thyroid function are no different from people who have partial thyroid function once their TSH is in normal range. Any normal level of TSH is good enough for every thyroid patient.

Even if it is theoretically possible that your symptoms and health conditions could be fixed with a higher T3 level in range, this would come at the cost of raising your T4 and even worse, lowering your TSH, which we would never do. Essentially, you do not have the right to attain a T3 level that is higher in reference range if your levothyroxine dose would then endanger your health.

So sorry, higher T3 levels within range are simply going to be unachievable or not permissible for you by raising your T4 dose, but that’s no big deal because we’ve fixed your TSH, and that’s our job.

We’ve played around with tweaking some people’s T3 levels with T4 therapy and even by adding tiny doses of T3 (without lowering TSH of course), but we haven’t had much success in helping them with these factors, on average. Therefore, we’ve largely given up on the idea that raising T3 levels makes a difference for the vast majority of our patients. 

We believe that some rare patients might benefit from combination T4-T3 therapy, but we’re really having a hard time identifying the few people who might benefit from the tiny little doses of T3 we are willing to give them.

(We are having a hard time identifying such patients because they would have to be a rare case whose symptoms can’t be blamed on anything else but LT4 monotherapy. The patient can’t be too sick or too old, because we think those conditions would make it less likely they’d benefit from T3. Who qualifies for a trial? It’s unthinkable for us to imagine giving T3 to everyone who complains of symptoms on LT4, or to everyone with a T3 below a certain level. No that’s way too easy, and that would open the floodgates. No, it has to be more difficult to find the right types of patients who we think might possibly benefit.)

American Thyroid Association-FeelHypo

Q8. What are the goals for levothyroxine therapy in people with secondary hypothyroidism?

A: If you are one of the 1:100,000 people who has central, pituitary or hypothalamic disorders that cause inappropriately low TSH, in that case we will have to ignore your TSH because it won’t behave normally.

Since we can’t use your TSH as a target, we will dose you to your levothyroxine so that your FT4 is in the upper half of reference range.

We really don’t care how low your FT3 levels go.

However, we will make absolutely sure your FT3 is never above reference range, which happened in one T4-T3 therapy trial in secondary hypo folks. (We had to put a stop to that, even though the therapy was more successful in every other way.) So, no combination therapy for you, because your T3 might go high.

We don’t care what your “clinical parameters” (symptoms) are. Since it can’t be about your TSH, it’s all about your T4.

We’re not against having your doctor monitor “tissue markers of thyroid hormone action,” but your T3 and T4 levels will always trump them.  We simply haven’t bothered to study whether other biochemical markers of thyroid hormone sufficiency could help us adjust your dose. (Why? because those tissue biomarkers were replaced by TSH long ago, and we’re not going to re-learn from history how to monitor your cholesterol or ankle reflex just because we can’t trust TSH in a few rare people with central hypothyroidism).

Q9. What do you think of patients who are unsatisfied or still have unresolved symptoms on levothyroxine?

A: We will all have to wait until a group of experts have developed a special clinical instrument or questionnaire that will measure your symptoms in a valid way

(It’s implied that this instrument has to be developed by the right “experts” who believe what we currently believe about symptoms. Such people are not in a rush. They will take their time and benefit from publishing journal articles about their questionnaires’ validity.)

We already like some tests and instruments more than others, so we’re recommending that those get attention.

But no matter what the results are of these surveys of symptoms and quality of life, we will always judge these results by looking at “more sensitive” and “hypothyroidism-specific tools” — namely, the TSH. By definition, this sensitive and specific biochemical tool is necessary to validate or invalidate the symptoms measured by a questionnaire.

In general, we know a “minority” of patients with normal TSH will perceive unclear symptoms that can’t be traced to thyroid hormone levels in any way because of their normal TSH. If you are in this minority, we will perform the role of the compassionate physician and listen and acknowledge your symptoms. Then we will diligently search for other medical causes than your thyroid hormones. We already know that increasing your L-T4 dose does not always help you get rid of your symptoms, and if more levothyroxine can’t solve it, it can’t be thyroidal.

Future research will tell us whether specific subgroups might benefit from combination T4-T3 therapy, but in the mean time, we won’t give you T3 just because you are suffering symptoms with a normal TSH. Outside of the context of a controlled clinical trial, we can’t really tell if giving T3 will really help you, because patients’ increased satisfaction on T3 could just be a placebo effect.

Q10a-d. Would we ever give levothyroxine to a person who has hypothyroid symptoms but has a normal TSH?

A: Of course not.  If your TSH is already normal, you are euthyroid regardless of symptoms, by our definition. You don’t need levothyroxine because a normal TSH means your thyroid hormones are fine. Even if you have many hypothyroid symptoms, are depressed, or are obese, or have hives (chronic urticaria), levothyroxine can’t help you because your TSH is already normal. 

Symptoms are confusing to us because they don’t seem to correlate with TSH. There are too many symptoms of hypothyroidism that overlap between people with high TSH and normal TSH, so we think that therefore they can’t be hypothyroid symptoms.

In general, depression in overt hypothyroid patients (untreated people with high TSH) is usually resolved with levothyroxine (normalized TSH). But even after successful therapy, there might still be a small connection between hypothyroidism and depression, since there is a slightly higher TSH on average in depressed people being treated with levothyroxine. But we looked at the numbers, and it was a difference between 1.9 and 1.5 on average, and that’s statistically insignificant, so we tend to believe it is clinically insignificant.

Among our treated patients, an underlying depression may be caused by thyroid disease and it might become paradoxically “unmasked” by treatment. In other words, if levothyroxine makes depression worse, it can’t be blamed on levo because the patient had latent depression before starting levo.

A thyroid patient’s sadness might just be caused by the difficulty of accepting the fact that they have a lifelong chronic disease and have to do the very difficult thing of taking one pill every day.

Now let’s deal with the way psychiatrists have a tradition of treating non-hypothyroid people with thyroid hormones if they are not responsive to antidepressants. The successes that clinical trials have seen in treating depression in euthyroid people with either overdoses of T4 or larger doses of T3 hormone like 37.5 mcg are likely no better than placebo because the trials weren’t designed to control for placebo effect. (We won’t talk about the fact that a dose of 37.5 mcg would certainly cause T3 fluctuations, nor the fact that these psychiatry trials didn’t mention any adverse effects from the T3 fluctuations that we think are unnatural and potentially harmful).

Overall, if we put you, a person with normal TSH, on levothyroxine, we are risking harm to you. We not only risk overdosing you on thyroid hormone, but we also risk deflecting medical attention away from your non-thyroidal health problems, including any imaginary “somatization disorders” by which you can make yourself feel sick.

As for hives, about 25% of people with chronic urticaria have autoimmune thyroid disease, so it could be connected to Hashimoto’s antibodies. In early Hashimoto’s, your thyroid gland may be dying but not dead enough yet to raise your TSH and make you deserve levo. Levothyroxine probably can’t remove the hives, and our job is limited to dosing levothyroxine in genuinely hypo people.

Q10e What will we do if we discover you’ve overdosed your meds?

A: If your lab test results make us suspect mistaken or intentional overdosing on any form of thyroid hormone (including some unregulated supplements sold in the US that contain thyroid gland extracts), we will stop your medication completely!

We will then either re-educate you or refer you to a psychiatrist, as the situation requires.

We call this “factitious thyrotoxicosis.” If it isn’t a pharmacy error or unintentional mistake, it is a psychiatric disorder. 

A serious mental problem might lead you to think that ingesting more thyroid hormone will help you. You might have a neurosis or poor body image because of your weight gain. You may be driven by “Munchausen’s syndrome,” a condition that makes you intentionally produce signs of illness.

[To be continued; See index of series at top]

REFERENCE

Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., … Sawka, A. M. (2014). Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid, 24(12), 1670–1751. https://doi.org/10.1089/thy.2014.0028

Related posts about guidelines, and the ATA



Categories: American Thyroid Association, T4-monotherapy, Therapy guidelines, Therapy paradigms, Thyroid pharma

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  1. Individual thyroid ranges are 38-68% the size of the lab reference range – Thyroid Patients Canada

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