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You can have a “normal” TSH and still feel terrible - stubborn weight that won’t budge, feeling cold, dry skin, thinning hair, swollen limbs… But your doctor says there’s nothing wrong with your thyroid.
There is nothing more frustrating….
Those of us who’ve spent years learning about hypothyroidism because we know there’s something wrong know that this scenario is all too common. Many of us have also been around long enough to know we’re not the only ones.
Unfortunately, there are many reasons this happens, not the least of which is doctors who have the standard bad training and/or bad attitudes when it comes to thyroid issues. Sadly, it’s common for GP’s to refuse to do the right tests, even when patients have done their research and specifically ask for them.
I was recently told by a young lady, who had some of the most obvious thyroid symptoms I’ve ever seen, that her doctor refused to test her T4 and T3 even when she offered to pay for the tests herself. I delighted in telling her she can order those tests herself online. She had no idea that she could order the tests without her doctor, which is (sadly) common in New Zealand. If you’re a reader in New Zealand, you can order your own labs via Pathlab’s MyWay Website, BodyIQ or I-Screen.
It can honestly be akin to pulling teeth to get the right tests done and a diagnosis of hypothyroidism from most GPs, and it’s mostly women who suffer due to this ignorance, bias or bloody-mindedness so often found in the medical profession.
So, as in my case, where I’ve known for decades, due to symptoms (and basal body temperature), that I’m hypothyroid, we manage our health the best we can and suffer the often debilitating consequences of a broken metabolism. Until maybe one day, if it gets bad enough, the almighty TSH test might actually prove what we’ve known for years.
Then all too often, once the relief of finally having a diagnosis is over, we realise the battle is only just beginning as we discover we have to fight with doctors to get the right medication that actually makes us feel better. I’ve never been through this part of the journey myself as I gave up on doctors years ago, but from the stories I’ve heard and read, questions about medication often result in something like this:
“No. We don’t offer T3 or natural desiccated thyroid. Levothyroxine is the standard of care, and if your labs say everything is normal, then it’s obviously all in your head. Here’s a script for an antidepressant…”
It - should - NOT - be - this - hard!
And now I’m ranting. Can you tell I’m a wee bit passionate about this? I am. And yet there’s more…
I recently learned about DIO1 and DIO2 genetic variants when I discovered that both myself and my husband have several. These variants can and do cause hypothyroidism symptoms by reducing the conversion of T4 to T3, and potentially increasing rT3 (reverse T3).
What amazed me is that I’ve never come across any reference to these variants in all my years of delving into information about low thyroid symptoms. In fact, I can say I’ve never heard anyone talk about them, even though they’ve been known and discussed in research papers for a couple of decades. They seem to be ignored by the medical community.
Here’s a rough timeline of their discovery:
DIO2 (rs225014 / Thr92Ala) was the earlier of the two variants to attract serious attention. The Canani paper linking it to reduced enzyme activity and insulin resistance in type 2 diabetes was published in 2005.
Then the landmark Panicker et al. study published in 2009 in the Journal of Clinical Endocrinology & Metabolism found that the CC genotype of rs225014 was associated with worse baseline psychological well-being in hypothyroid patients on T4-only therapy. It found that these patients had greater improvement when switched to T4/T3 combination therapy. That paper directly challenged levothyroxine monotherapy as a one-size-fits-all approach.
DIO1 (rs2235544) was examined around the same time by Panicker et al. A 2008 study found that the genetic variant rs2235544 in the DIO1 gene is strongly linked to differences in the balance between free T3 and free T4 thyroid hormones.
While the C-allele was linked to increased deiodinase 1 function, leading to higher free T3 and lower rT3, with no effect on TSH, the T-allele (also sometimes reported as the A-allele) has the opposite effect - lower free T3 and higher rT3, again with no effect on TSH.
And that last point is critical: TSH doesn’t move, which is exactly why standard testing misses this!
So the core evidence has been in peer-reviewed endocrinology journals since roughly 2008–2009. That’s nearly two decades, and means that this information has been available to endocrinologists for over 15 years...
The prevalence of the DIO2 (Thr92Ala) homozygous variant (homozygous means two copies) has been reported to affect 12.9–14.9% of the general population, and depending on the study, is found in 12–36% of the general population in at least one (heterozygous) copy.
The approximate distribution of the DIO1 variant is:
CC (homozygous common “high DIO1 activity pattern”) - 35–55% of the population have high conversion
CT (heterozygous) - 35–50% of the population have average conversion
TT (homozygous variant “lower DIO1 activity pattern”) - 5–15% of the population have low conversion
So it’s not super rare. The low-converting TT variant at up to 15% could be quite a chunk of every thyroid patient’s waiting room. But chances are your doctor knows nothing about it.
Genetic variants in DIO1 and DIO2 affect how efficiently your body converts inactive thyroid hormone (T4) into the active form (T3) that your cells actually use. If you carry these variants, conventional thyroid testing will miss the problem entirely.
Your thyroid gland produces mostly T4 and small amounts of T3. T4 is a prohormone with low biological activity that is converted into the more active hormone T3 in the liver, kidneys, and peripheral tissues by deiodinase enzymes, using different enzymes in different tissues.
The conversion of T4 to T3 occurs through two main pathways. DIO1 mainly handles this process in the liver and kidneys and helps regulate circulating thyroid hormone levels. DIO2 catalyses conversion within specific tissues such as the brain, pituitary, muscle, and heart, allowing local regulation of available thyroid hormone in addition to circulating thyroid hormone levels.
Reverse T3 (rT3) is sometimes referred to as the “decoy” thyroid hormone. It is an inactive form of thyroid hormone that increases when the body wants to preserve energy. During periods of low calorie intake or fasting, more T4 is converted into rT3 as part of a natural energy-conservation response.
rT3 is a protective adaptation that slows the thyroid effect. It is made from the same materials as T3 but has no metabolic activity. This is obviously beneficial in times of famine, but not great when we have plenty of food!
Your body increases rT3 when it wants to conserve energy, reduce metabolic rate, or survive stress or low fuel availability.
Common triggers for increased rT3 include:
Low calorie diets
Fasting
Chronic inflammation
Illness
High stress or cortisol
Nutrient deficiencies - especially selenium, zinc and iron
Reduced DIO1 activity
Everything that happens in your body is about balance. When it comes to metabolism, your body is constantly choosing between converting T4 to T3 to keep metabolism up, and converting T4 to rT3 to slow it down. The body produces more rT3 during stress, illness, or low energy availability to conserve resources. When rT3 rises, that’s the body deciding to ‘slow metabolism down right now’.
If someone continues to experience hypothyroid symptoms despite apparently normal thyroid blood tests (TSH, T4 and T3), rT3 may provide additional information about how thyroid hormone is being metabolised. Elevated rT3 can indicate that a greater proportion of T4 is being diverted away from the active T3 pathway. However, apparently researchers continue to debate the extent to which rT3 itself contributes to symptoms, which probably explains why it’s so difficult actually to get an rT3 test!
DIO1 mainly acts in the liver and kidneys, and it can have two opposite effects on T4: it can convert it to T3, or it can convert it to rT3. Think of DIO1 as a dial that helps control the balance between ‘energy up’ or ‘energy down’ depending on the body’s state.
DIO1 will increase rT3 under certain conditions, and for those of us with DIO1 genetic variants, this effect can be compounded. So let’s have a look at how this happens.
Before we get started with this section, I want to explain a couple of common terms for those who are new to the terms used when discussing genetic data.
The first is SNP - or Single Nucleotide Polymorphism. A SNP is a variation at a single location (one nucleotide position) in the DNA.
A gene is a much larger stretch of DNA and can be made up of hundreds or thousands of nucleotides.
A single gene can contain multiple SNPs. For example:
DIO1 is the gene
rs2235544 and rs11206244 are two different SNPs within that gene
Each SNP is just one spot where the DNA varies between people
The second term you need to know about is the Allele. An allele is one version of a gene.
You have two copies of each gene (one from each parent), so you have two alleles. Those two alleles can be the same version or different versions of that gene.
A simple example is a gene that affects eye colour. You get one allele from your mother and one from your father. There might be Allele A that codes for brown eyes and Allele B that codes for blue eyes. This means you could be:
AA (homozygous) - Two brown alleles resulting in brown eyes
AB (heterozygous) - One brown, one blue allele, which could result in blue or brown eyes
BB (homozygous) - Two blue alleles resulting in blue eyes
Every SNP has two alleles, but those alleles can be the same (homozygous) or different (heterozygous), resulting in potentially different effects depending on the gene and the combination of alleles.
Now, let’s get back to these DIO1 and DIO2 variants and how they may or may not affect the way your body functions…
DIO1 variants don't cause hypothyroidism in the conventional sense. TSH can remain entirely normal. But they can impair both the conversion of T4 to active T3 and the clearance of reverse T3, which competes with active T3 at receptor sites.
When DIO2 variants are present, intracellular T3 availability may be reduced even when serum T3 levels look adequate. In people who carry variants in both genes, and particularly when selenium status is low, the cumulative effect can produce a pattern that looks and feels like low thyroid function despite standard labs looking normal.
As discussed above, each SNP has two possible alleles, and because you inherit one copy from each parent, there are three possible genotype combinations.
For example, a C/T SNP can appear as:
CC (sometimes reported as GG by laboratories that use the opposite DNA strand)
CT (sometimes reported as GA)
TT (sometimes reported as AA)
This can make it confusing to compare results from different testing companies, but they are simply different ways of reporting the same underlying genetic information.
Studies have shown that those with CC homozygous alleles generally have better-than-average conversion of T4 to T3, meaning that they’re likely to have great T3 levels and the benefits that result from that.
Those with CT heterozygous alleles are in the middle ‘normal’ conversion range.
And those of us with TT homozygous alleles (which may be reported as AA in your raw DNA data) are more likely to be deficient in T3 depending on nutritional status, stress and overall health.
Now let’s take a look at ways to manage the effects of these genetic variants using nutrition and other therapies.
The most important single nutrient for DIO1 and DIO2 function is selenium. Selenoproteins are the backbone of both enzymes. If you have these genetic variants and are low on selenium, then your ability to convert T4 to T3 is likely to be lacking.
For those of us with confirmed DIO1 and/or DIO2 variants, especially if we’re homozygous for the most impactful variants and have hypothyroid symptoms, testing our selenium level is important, helping us decide whether to supplement or not.
Warning: Too much selenium is toxic and can be hazardous to your health! Getting tested so you know where you’re at with this mineral is important.
It seems that iodine is always a hot topic. Ask anyone in the street which mineral is most important for the thyroid, and I can guarantee that almost all will say iodine. Very few people understand the importance of selenium.
Iodine IS important! In fact, it’s essential. But without adequate selenium, iodine can literally be dangerous. I wrote an article explaining this recently, so I won’t go into it again.
The short version is that if you take iodine with insufficient selenium, your thyroid can be damaged over time by hydrogen peroxide, a byproduct made by your thyroid when using iodine, and you may also end up hyperthyroid just as I did many years ago. That particular part of my story is included in the article linked above.
I realised I was homozygous for rs2235544 and heterozygous for rs11206244 a few months ago when I put my Ancestry DNA data file into Claude.ai. I’d been digging into my genetics for a couple of years, using various free and cheap tools to uncover the genetic variants that explained so much about the way my body and brain function. But because I’d never heard of DIO1 or DIO2, I didn’t know to search for them.
But Claude.ai, being able to read the complete data file, uncovered these variants and opened up a whole new level of understanding for me. It introduced me to the DIO1 and DIO2 variants, and I learned that I have two hits on DIO1 but at different positions, compounding the conversion issue.
When I learned this information, my life and my health challenges began to make more sense, and the lifelong symptoms and intuition that were telling me I’d been hypothyroid most of my life were confirmed.
I grew up in New Zealand, where soil selenium levels are extremely low, and I’ve lived here off and on as an adult (Australia the rest of the time), with the latest stay being over ten years at the time of writing.
I’d noticed over the years that I seemed to struggle more with my health and weight while living in NZ compared to Australia. But I put that down to the difference in sunshine and lifestyle. Now I know there’s probably more to it.
Australia has higher selenium levels in some areas, and generally better levels overall than NZ. So although I have no doubt I spent a lot of years without optimal selenium levels while living there due to my vegan and vegetarian diets, my selenium level may still have been slightly higher.
And while low selenium can impact thyroid hormone in everyone, those with DIO1 and DIO2 variants may be impacted more.
I also discovered via Claude and Ancestry data that while my husband is homozygous for rs2235544, the same as me, he is also heterozygous for the most studied DIO2 variant, rs225014 (also called the Thr92Ala variant), which affects T3 levels in the brain and muscles.
DIO2 (type 2 deiodinase) converts T4 to T3 primarily in the brain, pituitary, skeletal muscle, and heart tissues. The key variant is rs225014 (Thr92Ala). This is the most studied DIO2 polymorphism.
The pituitary uses DIO2, so if DIO2 is impaired, TSH can be falsely reassuring. Even with adequate circulating T3, the brain may be starved of it and cause cognitive symptoms, depression, and mood dysregulation.
And as in my husband’s case, the lack of intercellular T3 can also cause chronic muscle fatigue.
Studies show worse outcomes on T4-only therapy for DIO2 carriers, and better responses to a T4/T3 combination therapy.
For those like my husband who carry both DIO1 and DIO2 variants (as many people do), they may be experiencing both peripheral conversion impairment and central conversion impairment.
The clinical picture for these people is that their symptoms are often dismissed as anxiety, depression, or “just getting older”, as symptoms worsen with age. And if they’re eventually diagnosed with hypothyroidism, they ultimately fail on levothyroxine monotherapy because the medication isn’t doing anything to resolve the underlying problem, which is the conversion issue.
So this combo of effects also explains some things for my husband which I won’t go into here, but it’s great to have more understanding of his physiology!
We’re now both supplementing selenium and noticing some good changes (mainly feeling warmer) even though we’ve only been taking it for about eight weeks at the time of writing. Apparently it can take three or four months to get levels up to an optimal range. (I wonder if that might happen faster for me because I’m now eating fish most days, whereas my husband eats no seafood at all - ever. We will see when we get tested.)
When supplementing selenium, Selenomethionine is the most readily used by the body. Hubby and I are both currently taking 100mcg a day and will adjust if necessary once we retest our selenium levels.
Apart from selenium, the following is a list of nutrients and lifestyle factors that are essential for healthy thyroid function:
Zinc is a cofactor for thyroid hormone synthesis and conversion. It is commonly depleted in high-stress, gut-compromised individuals.
Iron is required for thyroid peroxidase activity. Low ferritin impairs the whole cascade.
Iodine is necessary but double-edged. Excess without adequate selenium drives rT3 and can trigger Jod-Basedow in susceptible individuals. (This was my personal experience).
Vitamin A regulates thyroid receptor expression.
Magnesium supports T4 to T3 conversion indirectly via enzyme function. Magnesium Glycinate is my preferred variety.
Protein adequacy is important. Deiodinase enzymes are selenoproteins, and so insufficient protein supply limits synthesis.
Gut health. Approximately 20% of T4 conversion happens in the gut; dysbiosis impairs it.
Stress and cortisol. Chronic stress shifts the T4 to rT3 pathway, causing more rT3 via the HPA-thyroid axis interaction
Sleep and circadian timing are super important. Thyroid hormone secretion is circadian, and disrupted sleep raises rT3.
From what I’ve learned, the first and most important step is ensuring that selenium is optimal (1.6-1.9 umol/L according to Rayman MP. Selenium and health. Lancet 2012; 379: 1256-68). These enzymes are selenium dependant and if you’re lacking selenium, they can’t do their job.
The next step is making sure you’re getting the other essential nutrients listed above, reducing and/or managing stress, getting quality sleep, sun in your eyes in the morning, and avoiding blue light at night. These are the bare essentials for circadian health.
The final option is taking some form of T3. This, of course, is an option that may, or may not, be difficult to arrange, depending on your doctor. (Hubby and I haven’t gone down that route yet as we’d prefer not to mess around with hormones, and would like to see how far we can get with nutrition and lifestyle first).
The various T3 options include synthetic T3 on its own, T4/T3 combination therapy, NDT or Natural Dessicated Thyroid and thyroid glandular supplements. From everything I’ve seen over the years, it can take some experimentation to find the right option and dosage to suit your individual physiology.
If you’re reading this and wondering whether you might have these variants, you have a couple of options. You can have testing done via one of the many businesses online that specialise in genetic testing (these are often expensive, so make sure first that they actually test for these genes before you order).
Or you can do as I did and have your DNA tested by Ancestry or 23andMe and then investigate yourself.
If you decide to go the cheaper route, once you have your genetic data file, you can either search for the rsIDs in the file, or you can upload the file to Claude.ai and ask it to analyse the data for you. The Ancestry and Claude route is my personal preferred option, because I can continue to ask questions forever after. I have a curious mind and always so many questions.
I do have one warning, however. When using AI for this type of thing, ask it to double-check and then triple-check, as it does make mistakes and sometimes provides answers based on assumptions.
Key rsIDs to look up: rs2235544, rs11206244 (DIO1); rs225014 (DIO2)
Even though for some of us, low thyroid symptoms have been lifelong, discovering that we have these variants can be a huge blessing. Once we know what we’re dealing with, things make sense, and we can have more control over our health.
I personally feel blessed to finally have more understanding and knowledge, and to know that I can take steps to improve my T3 levels.
With the right nutritional support, testing, and, where necessary, T3 replacement therapy, poor converters can function well and reduce their symptoms.
Don’t ever forget that selenium is the most important nutrient for those of us with these genetic variants. Including foods that contain good levels of selenium is important, and a vegan or vegetarian diet probably won’t do you any favours. The following are the best food sources of selenium:
Seafood: tuna, sardines, salmon, oysters, shrimp provide up to 5 µg/g;
Beef kidney (4.5 µg/g)
Beef Liver (0.93 µg/g)
Beef Heart (0.55 µg/g) ResearchGate
Beef: bottom round steak provides ~33 mcg per 3 oz (~60% of daily need) Johns Hopkins University
Eggs: selenium is concentrated in the egg white Johns Hopkins University
Cottage cheese: one cup provides ~20 mcg
Brazil nuts can be one of the highest sources of selenium, but it pays to be wary, as even one nut can exceed daily requirements. It’s hard to know how much selenium you’re getting with Brazil nuts, so eating them daily is not recommended.
Meat and seafood are both more reliable than plant-based sources of selenium because they're protein-bound. However, land-based meat and eggs still depend on livestock feed quality and regional soil selenium levels, whereas seafood provides more consistent selenium due to uniform ocean selenium concentrations.
Selenomethionine (the organic form) has an absorption rate of over 90%, compared with about 50% for selenite. Selenomethionine is often recommended for thyroid patients due to its benefits for thyroid health.
Selenium-enriched yeast naturally incorporates selenium into proteins predominantly as selenomethionine (60-85% of total selenium) and is another good option.
Sodium selenite/selenate is inorganic and best avoided. It has an approximate 50% absorption rate and causes oxidative stress.
According to research, a safe and effective range is generally 50-150 mcg daily. Avoid exceeding 400 mcg/day of selenium from all sources.
It makes sense to me that we should test before and during selenium supplementation, as this mineral, while essential and beneficial, can be toxic if levels get too high.
The practical guidance is to test first if possible (this avoids unnecessary supplementation), and then supplement if your levels are low. Retest in 2-3 months to verify improvement, then annually after that.
Most people don't need to supplement if eating adequate protein-based foods.
If you have any comments or questions, feel free to leave them below.
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