In this series, I am examining two T4-T3 thyroid hormone ratios that have been circulating in thyroid medical literature for decades.
The first ratio is the “molar ratio” of T4 and T3 hormone secretion from the thyroid gland. The second ratio is the theory that the human body derives 20% of its T3 hormone supply from the gland and 80% of its T3 from T4-T3 conversion outside the thyroid.
Both of these ratios can be traced back to the averages and numbers given in a single article.
The article by Alessandro Pilo and several colleagues in 1990 was titled “Thyroidal and peripheral production of 3,5,3’-triiodothyronine in humans by multicompartmental analysis.” (3,5,3’-triiodothyronine = T3)
HOW INFLUENTIAL IS PILO’S ARTICLE?
Pilo’s article has been officially cited by 121 scientific sources as of May 27, 2019, according to Scopus, a highly-respected database that tracks citations in scientific publications.
Those 121 sources have themselves have citation statistics in Scopus totalling 5,727 citations.**
This means that Pilo et al’s 1990 research article has had a significant “reach.”
Therefore, it really matters WHAT Pilo’s article says.
It also really matters HOW people use Pilo’s article:
- — presumptions that frame their research design and purpose
- — tools to help interpret their data or results
- — principles to guide thyroid therapy
- — tools to attack or praise thyroid hormone medications
- — tools to justify testing or not testing certain hormone levels
PILO’S STUDY LIMITATIONS
There’s nothing intrinsically wrong with the article. It’s just a research experiment that yielded some insight about what happens when you test 14 human beings using some very complicated methods and mathematics.
However, there’s a lot wrong with not reading it carefully to understand its limitations.
Here are 3 key limitations that only the best researchers will notice.
1 — PATIENT POPULATION: Pilo et al’s article did not promote the many unfair applications of their research to the treatment of hypothyroid patients.
The article is highly exploratory and tentative in its wording. However, endocrinologists have not employed it in an exploratory or tentative way, but rather as dictators of limits and targets.
The article never based its findings on people with damaged or missing thyroids who are taking thyroid hormones, and it did not even suggest applying its findings to them.
But endocrinologists chose to apply this study to very different patient populations than the people Pilo studied — those happen to be vulnerable people with a disease, millions of people worldwide whose thyroid hormone intake and blood levels are subject to their control.
2 — AVERAGES ARE CONVENIENT BUT DECEPTIVE: As you’ll see in my earlier post, human thyroid glands secrete a wide range of T4 and T3. The conversion rate of T4 to T3 also varies widely.
Why did Pilo and his team sometimes used averages instead of ranges to express T4:T3 thyroid secretion and T4-T3 conversion? Averages are convenient and efficient for certain purposes.
Pilo’s figures were extremely complex and did not often have room for ranges. They would be even more puzzling than they already are if they included ranges.
In addition, Pilo and team could do certain types of mathematical calculations with an average that they simply could not do with a range.
For the same reason, people have found it convenient to cite an average like 15:1 and 20% / 80%, but the reality in human physiology is actually a wider range.
3 — IT’S NOT A PHARMACEUTICAL STUDY. The article never discussed the ratio of hormones found in thyroid hormone pharmaceuticals. But the ratios of hormone it found in the body have been used to justify or attack hormone ratios in drugs.
If you believe that pharmaceuticals ought to imitate an average gland secretion ratio, that’s a philosophical stance. This article didn’t make an argument to support your philosophy of medicine.
WHAT PILO DID NOT SAY
In addition to the three limitations above, there are at least six major misinterpretations. These are ways in which people have ignored its limitations, twisted its logic, and imagined it supported their own beliefs.
Each of these misinterpretations can potentially lead to harm.
1 — AN INDIVIDUAL IS AN AVERAGE?? No, Pilo’s research team did NOT say that every human being, including the individual thyroid patient sitting in a doctor’s office, gets 20% of her T3 from her thyroid and 80% of her T3 from T4 that is converted outside of her thyroid gland.
In FACT, you can’t take any statistical average and apply it to a single patient. You can’t say “If you have any thyroid gland tissue in your neck, it is right now secreting at a 14:1 ratio.” No. You also can’t say “If you are a human being, your organs are converting T4 into T3 at the average rate at all times.” You have no basis in Pilo for such ridiculous beliefs.
In FACT, statistical averages should not even be targets for health. Does a human body aspire to secrete everything at the average rate? No. Each body takes care of its own needs and isn’t looking at the population stats to judge how much it should have. Also, can the average ever define perfect health? What if the average population is very unhealthy?
2 — YOU’LL BE FINE ON T4 THERAPY WITHOUT A THYROID?? No, Pilo et al did NOT say that it’s no big deal if you have no thyroid or it’s a dead mass of tissue.
In FACT, he did not say that the your body will increase its rate of thyroid hormone conversion by 20% to make up for your permanent handicap. That’s nowhere in the article.
In FACT, he did not study thyroid disease or therapy in this article. He studied a narrow range of thyroid health, 14 people with a TSH between 1 and 2 mU/L. You can’t necessarily apply a finding from a thyroid-healthy group to a thyroidless or thyroid-damaged group. Their body’s feedback systems function differently without that gland, and certain systems may adapt poorly to artificial static dosing rates and ratios.
3 — MOST OF YOUR T3 SUPPLY IS HIDDEN FROM BLOOD TESTS?? No, Pilo et al did NOT say that only 20% of T3 is measurable in bloodstream, while 80% of a person’s T3 hormone is unmeasurable in thyroid blood tests because it is located in tissues and hidden in cells where blood tests can’t measure it.
In FACT, Pilo’s article talks about the way bloodstream and tissue “exchange” their T4 and T3 content with each other. Thyroid hormone transport goes two ways across cell walls. The T4 and T3 hormones (and Reverse T3) go into cells and back out again into bloodstream. There is no gate keeping a big secret stockpile of thyroid hormones from coming out of cells.
In FACT, Pilo’s model assumed that fast-exchanging tissue pools exchange faster than the slow-exchanging tissues, but they all exchange intracellular tissue levels with bloodstream.
4 — T4-T3 CONVERSION IS THE SAME IN EVERY ORGAN?? No, Pilo et al did NOT say that every organ converts T4 into T3 hormone at the same rate, and that therefore the pituitary gland’s rate of conversion from T4 to T3 thyroid hormone represents the rate found in every other gland in the human body.
In FACT, we know the opposite to be true. The liver and kidney convert T4 hormone at a different rate than skeletal muscle and heart, even in rats. Pituitary secretion of TSH is a very complex response. There is no other human organ or system that responds to thyroid hormones the way that the hypothalamus and pituitary do. It is always possible for one organ to be hypothyroid while another organ is not.
5 — LOW T3 IN BLOOD IS HARMLESS?? No, Pilo et al did NOT say (and this matters to human health) that the body will be just fine if we have low Free T3 in bloodstream as long as our Free T4 supply is in normal reference range and our TSH is in normal reference range.
In FACT, Pilo did not discuss the sensitivity and accuracy of any of our current laboratory testing technologies.
In FACT, Pilo did not engage with the controversies about how Free T3 and Free T4 reference range cutoffs are determined. He can’t tell you whether the low reference cutoff is too low based on blood samples of persons with illnesses, medications and other metabolic disturbances that lower their T3 hormone supply.
In FACT, Pilo’s article says the opposite. Based on prior research, it reasons that T3 sufficiency in blood is extremely important, and T3 deficiency in blood can be very harmful.
Read this quote from Pilo carefully:
“About two-thirds of the T3 contained in peripheral tissues does not arise from local conversion. In particular, tissues such as skeletal muscle and the gastrointestinal tissue (together accounting for 40% of total body mass) which are known to exchange with plasma slowly, appear to derive T3 almost completely from the plasma itself.”
What does this quote mean?
Something quite important for thyroid patients who are being forced to maintain Free T3 levels very low in reference or below reference range for months or years.
If endocrinologists were to take this quotation from Pilo et al as gospel as much as the average ratios of secretion and conversion, how could they ever dismiss below-range or low-normal Free T3 in blood that yields symptoms in particular organs and tissues?
Based on Pilo, any doctor who dismisses a chronically low T3 level in blood could be dismissing the needs of the skeletal muscle and the gastrointestinal tissues, accounting for 40% of a thyroid patient’s body mass. This is regardless of what their FT4 and TSH levels say, because these tissues depend a lot on T3 from blood, less on T3 from conversion.
6 — THYROID THERAPY SHOULD OBEY THESE RATIOS. No. No. Never, no.
In FACT, this research team was not writing guidelines for therapy or tips for pharmaceutical manufacturers.
Pilo et al didn’t write prescriptions.
Yet this article’s average ratio of 14:1 (T4:T3) has been used to attack a disfavored pharmaceutical (desiccated thyroid) for its higher T3 and lower T4 hormone content without pointing out how UNphysiological T4-monotherapy is at a ratio of 100:1.
Yet the article’s average 20% secretion and 80% conversion rate has been used to validate endocrinology’s favorite thyroid pharmaceutical which contains no T3 at all, and their favored T4-only pharmaceutical is used in people who have a 0% secretion and ??% unpredictable conversion rate that varies widely from individual to individual.
The ratio of 14:1 has been used to rig T4-T3 combination studies, limiting them to tiny little doses of T3, fearing that adding more will make all patients thyrotoxic. (All? Yes, they point to the peak Free T3 that occurs transiently for 2-4 hours post-dose in the fluctuations of this therapy without checking to see if the net 24h supply is capable of being thyrotoxic.)
Those who want to keep the status quo of “miniT3-combination” thyroid therapy focused on a 14:1 to 20:1 (T4:T3) medication ratio don’t want to end up proving that adding MORE T3 than this ratio may truly be “superior” for those patients who convert T4 very poorly.
And, finally —
In FACT, this research team was not supplying a legal disclaimer to cover the butts of health care systems that want to save money on T3 prescriptions and Free T3 tests.
Yet today in the UK, these ratios are being used to take away T3 hormone therapy from patients who do not fare well on T4 monotherapy, and to limit their T3 hormone dosage.
Yet today in Canada and UK and other countries, the simpleminded belief that “we all get enough T3 from T4” is being used to justify CANCELLING Free T3 tests.
An unethical medical system does not want to find out if or when their thyroid patients are low in Free T3 range or below its reference (“We didn’t measure Free T3, so we can’t be held responsible for not acting on that data”). So the system blinds itself by never measuring.
Seriously? Even Pilo measured Free T3, back when the test was in its earlier phases of development. And you’re trusting and depending on his data.
An unethical medical system does not want to believe or admit it is harming people by withdrawing medications or tests, so it says that all the patient’s hypothyroid symptoms and worsened health conditions have nothing to do with their thyroid hormone levels — because Pilo says you’ll get 80% of a normal person’s T3 supply? No, he didn’t study T4-treated patients in this study.
Pilo et al didn’t write excuses for T3 evidence denial or T3 medication withdrawal.
All who misuse Pilo’s study in this way are ideologically and economically motivated, not motivated by a search for truth or health.
This is one of the most unethical misuses of research findings ever — to justify human suffering and to justify blindness to a chronic T3 deficiency. All for the sake of what? To obtain economic savings and to uphold a pharmaceutical prejudice.
– Tania S. Smith
Pilo, A., Iervasi, G., Vitek, F., Ferdeghini, M., Cazzuola, F., & Bianchi, R. (1990). Thyroidal and peripheral production of 3,5,3’-triiodothyronine in humans by multicompartmental analysis. The American Journal of Physiology, 258(4 Pt 1), E715-726. https://doi.org/10.1152/ajpendo.1990.258.4.E715
CITATION STATS: Scopus is a database that’s only accessible if you are a paying user or member of a university or institution that pays for access. Therefore, I’ve compiled the information for you in this Google Sheet — in desktop view: https://docs.google.com/spreadsheets/d/1nNb6dR7yTeYS0N_NOlYqs25wClY5ZyjgbZ1QQrLG4Nc/edit#gid=0