Low-T3: The huge and horrible gap in thyroid research

Many studies have been done on patients whose T3 levels are below lab reference ranges despite a TSH and T4 within range. Most of them have discovered that low serum Free T3 is a dangerous factor to have when one is ill: it is often an independent predictor of morbidity and mortality in patients with organ failure such as heart disease, liver disease and kidney disease. (See my review in this post on the Dangers of Low T3.)

The problem is that such research studies usually exclude patients diagnosed with hypothyroidism.  Why?  They always say it is to avoid confounding factors. Researchers have been mainly intrigued by the puzzle of hormonal dysregulation in patients who have a normal, functional thyroid. Studying hormone dysregulation in people with abnormal thyroids is less paradoxical and potentially more complicated.

Certainly, it is a fact and a mystery that a significant number of deeply ill patients get “low T3 syndrome.” For years researchers suspected that it was an adaptive (positive, protective) response to illness, rather than a maladaptive or dangerous condition.

But years of many research studies is making more and more researchers suspect that having Low T3 is not a good thing, especially for critically ill people.  It makes them more likely to die or stay ill.

However, thyroid hormonal dysfunction can occur whether or not your thyroid gland is healthy, and whether or not you are currently ill. Thyroid hormone metabolism occurs throughout the body every hour of every day. Whether you get your thyroid hormones from a functioning thyroid gland or from T4 pills, your body still has to convert those hormones into the active hormone, T3.  Even a normally functioning thyroid gland does not produce sufficent T3 for anyone’s needs.  Hormonal conversion of T4 in the liver and cells is necessary for cells to receive proper levels of T3. Conversion to T3 has to occur at the proper rate for every organ and cell so as to avoid hyperthyroidism or hypothyroidism at the cellular level. Conversion of hormones is continually necessary in everybody. It can become dysfunctional in anybody.

It is well known that patients on T4 therapy often have lower serum T3 levels than expected given a high T4 level and normal TSH level.  Some patients on T4 therapy have laboratory values that are just as low as chronically ill Low T3 patients– below the lab reference range for FT3.  In those patients, increasing T4 does not result in increased T3, but can actually decrease serum T3. In apparently “healthy” Low T3 patients, hormonal dysfunction is obviously not caused by illness.  It could be an effect of treating their glandular hypofunction with T4 only, when a normal thyroid gland produces all the thyroid hormones, 85% T4 and about 10-13% T3, and some trace amounts of T2 and T1.

The “Low-T3 on levothyroxine (T4)” population is potentially huge, according to research by Midgley, et al, (2015). (See my summary and review of Midgley et al’s article in a post called “Thyroxine monotherapy and poor T4-T3 conversion.“) Millions of people are being treated with thyroxine therapy. A significant number could have chronically Low T3 (below lab reference range) despite normal TSH (sometimes) and/or normal-high T4.

Since all of us depend on cellular T4-T3 hormone conversion for health, I believe it is a moral and disciplinary failure of endocrinology researchers to continue to exclude a large population of patients from studies on their low-T3 state.

Since the 1990s, a continual refrain in research has been “we don’t know if chronic long-term low T3 is a risk factor” or cause of various chronic illnesses such as heart disease, liver disease, kidney disease, etc. If we don’t know, we should try to find out.

I am one of those patients who had chronically low T3 for many years, despite changes thyroxine dose after losing a lot of excess weight in 2012.  Over 3 years of testing and 9 thyroid blood tests, even when my TSH was below range (indicating T4 overdose), my T3 did not rise below the lower laboratory cutoff, as it logically should have. (See my graph of lab results.)  My doctor did what most are told to do: she aimed to normalize my TSH numbers by adjusting T4 dose, and ignored my illogically low T3 results. I was without adverse symptoms for many years with low T3, perhaps due to youth, a good diet, a healthy lifestyle, etc.  Even my ankylosing spondylitis arthritis condition had been in complete remission in my joints and eyes for three years since changing to a paleo diet in 2012.

Then in 2016 I experienced an onslaught of arthritis, acne, hypothyroid brain symptoms (cognition, mood, fatigue), and worst of all — when I tried an increased T4 dose, I immediately started having vascular spasm pain in my peripheral arteries branching off my aorta, causing dizziness, adjacent limb numbness or  weakness, etc.  It caused problems standing, walking, and driving, and the unexpected and random painful spasms reduced my ability to function normally. The vascular pain was difficult to explain at the age of 46, in the absence of all other cardiovascular risk factors besides hypothyroidism and hypercholesteremia. All the heart tests came back normal, and when chest arthritis was suspected, Diclofenac arthritis meds merely added GI side-effects.  I experienced 2 months of daily frequent pain while I and my doctors tried to understand and resolve these problems.

During these months, three times I tried adjusting my T4 dose slightly to see what it would do.

  • Lowering T4 dose by even 6.5mcg per day brought several days to 1 week of remission before the symptoms were back to prior intensity and frequency despite remaining on the lower dose.
  • For a while, I was on a dose between two pill strengths, 100mcg one day and 112 mcg the next day, until I noticed in my pain diary that my symptoms were worse every other day.  After I decided to stay with the lower dose, these fluctuations went away.
  • All three times I increased T4 dose slightly (the 2nd and 3rd times out of fear of hypothyroidism, and return of symptoms making me doubt T4 could be the issue). Within 36 hours of the higher dose, I was in such pain that I was compelled to go to the emergency room again.

After all the heart tests came back normal, a hormone specialist MD considered it safe for me to try a gradual shift from T4 to T3 medication step by step over the next two months.

  • Merely adding 5 mcg of T3 reduced my pain by 1/4 in the first week of the new therapy.
  • Gradually, increasing T3 medication solved the problems, reversing my symptoms by degrees every 2 weeks on the schedule when I made a slight increase in T3 dose and decrease in T4 dose.
  • Now, on T3-only therapy, I am completely “back to normal” and feeling healthy.

Admittedly, I am only one case. However, other causes of these symptoms were ruled out, and only T4 and T3 dosages made a significant difference in symptoms.  The logic is simple. T4 made my symptoms worse.  Reducing T4 made my health temporarily better but did not fix the problem. Replacing T4 with T3 made a lasting positive difference.

More research is necessary.

The kinds of research that could resolve this extended T3 “controversy” may include

  • Longitudinal population research studies on T4-treated patients with low-T3.  Are chronically Low-T3 persons more likely to become ill with certain illnesses?  If or when they become ill, do they experience problems with delayed recovery or worsening health? It should be relatively easy to find out through a historical study of a large number of patients whose TSH, T4 and T3 levels have been tested over decades.
  • Inclusive studies of T3 treatment of Low T3 in chronic or acute illness.  Does T3 therapy (or a gradual switch from T4 therapy to T3 therapy) aid in the recovery of ALL chronically ill patients with Low T3, regardless of the status of their thyroid gland?

It is time to include people with compromised thyroid glands in studies on Low T3.

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