Undertake any search of ‘consequences of hypothyroidism’ and you will reliably receive a laundry list of the usual symptoms; fatigue, brain fog, low mood, constipation, sensitivity to the cold, reduced hair growth and general malaise. However, the impact of hypothyroidism in the human body cannot be overstated and go well beyond these common signs. Thyroid hormones are the fundamental controller of metabolic activity in every single cell and therefore have a huge influence on the function of all organ systems, with particularly noticeable effects on energy-intensive organs (such as the brain) and energy-intensive processes (notably any course of healing, which evolution dictates can only occur with available energy that is leftover after survival-related processes have taken their share).
That being said, it is these symptoms that flags the issues in question and prompts individuals to connect with their doctor, doing so in order that they can get tested and then receive adequate treatment. It is therefore a cruel irony that the main obstacle to this end goal is the test itself, which fails to detect hypothyroidism in anyone with substantial metabolic challenges. The real kicker is that hypothyroidism is both a consequence and a driver of metabolic challenges, which is to say that the people with the most imbalances are also those least likely to show disturbances in their blood levels. Put another way, the archaic state of medical paradigms means that the people who are in most need of thyroid support are the people who are least likely to get it.
How can this be the case? I see this as a combination of the usual factors: too much dogma and outdated teaching, with insufficient curiosity from doctors to change things from the bottom up and insufficient financial incentives to change things from the top down.
We’ve known for years that thyroid testing is inadequate
Getting actual measurement of thyroid status of cells is difficult but this was done by Arem et al via an autopsy study of individuals who suffered from ‘non-thyroid illness’ and assessed the actual amount of thyroid hormones in tissues. The individuals studied all had normal TSH, T4 and T3 levels in circulation, yet were found to have a marked reduction in the level of thyroid hormones in tissues compared to controls (individuals who experienced no illness before death). T4 levels were 10% lower in the cerebral cortex and 67% lower at the liver. When they measured T3 levels, this difference was even more pronounced, with a 55% drop in the cerebral cortex and a 76% drop at the liver.
- Takeaway: thyroid entry to cells is reduced in individuals with metabolic challenges and therefore blood levels are likely to be a highly inaccurate measure of what is actually going on.
A further paper shows us that its not just about chronic illness and that just dieting alone can have important effects on thyroid uptake. They used radioactive tracers to determine both circulating and cellular levels of thyroid hormones and found that low calorific intake induced lower serum levels of T3 (“low T3 syndrome”), but the real kicker was that both T4 and T3 moved into cells much slower. 50% and 25% slower, respectively. It pays to emphasize that there are two sides to this coin; not only do we see less thyroid hormones in the cell (where we want them), but the serum levels are artificially raised. Similar research expanded on this by showing similar problems in cellular uptake of thyroid hormones across the body but, crucially, shows that this does not happen at the pituitary (which just so happens to be the zone that determines TSH output). Additionally the pituitary has its own enzyme system to form T3, protecting it from the ‘low T3 syndrome’. This explains why the cells can be subject to major starvation of thyroid hormones while TSH levels remain entirely normal.
- Takeaways: dieting reducing thyroid entry to cells but without affecting the pituitary and further underscores why blood levels may not give us the full picture.
Further research helps us expand on how this happens. In this experiment, Sarne et al bathed cells in the serum taken from groups that included healthy controls and those with ‘non-thyroid illness’. They found that the source of the serum had a big impact on cellular update; when the culture was provided with blood from those subject to metabolic dysfunction, the cellular update dropped.
- Takeaways: serum levels do not necessarily equate to cellular levels and there are substances in the bloodstream that drive this problem.
There are some massive implications from these four studies alone and, equally, some major questions. First let’s consider how all of these papers were published between 1985 and 1993. These are not new papers and this is not new knowledge. Yet application of this information is almost entirely absent in modern medicine, whereby doctors continually order the good ol’ TSH-and-T4 combo and then have the gall to tell suffering patients that ‘everything is OK’. It is of course possible that everything is fine but, should there be major metabolic problems, the chances of finding these are extremely low. In fact, a 1982 paper had already clearly demonstrated that TSH was likely to be of little use in assessing true thyroid status. How many more years will patients need to wait before they receive adequate support?
- Takeaways: modern medicine is using testing methods that are at least 40 years out of date and patients are suffering unnecessarily.
Building a mechanistic map of cellular hypothyroidism: causes and solutions
It is no surprise that, in the four decades since some of these studies came to the fore, our knowledge of the causative factors has progressed substantially. Studies (here and here) have identified 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF), indoxyl sulfate, hippuric acid, bilirubin and free fatty acids as reliable inhibitors of thyroid uptake into cells. Energy status (availability of ATP) also has a fundamental effect on thyroid uptake. This is particularly relevant when building a mechanistic understanding of this problem; doing so allows us to understand how it comes about, when it may distort thyroid panel results and what we should do about it.
So what do we need to know about these metabolites?
CMPF is a metabolite of fatty acids that, under ideal circumstances, should be quickly filtered by the kidneys. Understanding of CMPF is still in its infancy although its relationship to oxidative stress appears key and, like most reactive oxygen species, it can induce some positive effects at the right dose but becomes problematic as concentrations rise. Raised levels of CMPF are associated with both fatty liver, insulin resistance and inflammatory disorders like multiple sclerosis. CMPF is not offered by the functional labs, and requires specialist testing.
Indoxyl sulfate is a metabolite formed from the fermentation of amino acids in the gut (which then undergo transformation in the liver). Therefore, levels can rise due to dysbiosis, although it is also removed via the kidneys (and thus levels can rise in kidney disorders). Like CMPF, it is an item that needs to be removed by the kidneys yet it happens to impair the removal process here. Indoxyl sulfate measurements are not typically offered by functional labs, although we can easily measure indicans as a surrogate.
Hippuric acid is formed from the breakdown of dietary polyphenols and also a metabolic product of E coli. Yet again, it is normally removed quickly by the kidneys but therefore may accumulate in cases of poor kidney function (eg. uremia) or when intestinal populations of E Coli become excessive. It is one of the metabolites measured on Organic Acids test.
Bilirubin is a pigment that influences the colour of our stools. It is formed from the breakdown of haemoglobin and has antioxidant effects, especially relevant during hypoxia. Sustained hypoxia can increase its formation, as can haemolytic anaemia, although the most common cause of raised bilirubin relate to bile duct obstruction or other liver conditions that affect the elimination of bilirubin. Bilirubin is included in most basic blood panels.
Free fatty acids, also called non-esterified fatty acids, simply relate to a form of fats that are derived from dietary fat or those released from our fat cells (and, as the name suggests, are found circulating freely in our bloodstream rather than bound to cholesterol). They are already a key checkpoint in metabolic problems as they are shown to reliably induce insulin resistance. Specifically, they are considered the causative link between obesity and insulin resistance; this is because the fuller the fat cell, the more it ‘leaks’ fatty acids into the circulation, which causes little problems at baseline but creates a duel energy overload (both fatty acids and glucose) after carbohydrate intake, thus forcing liver and muscle cells into a ‘protective’ insulin resistance. They are also increased in response to sleep deprivation, a common obstacle for many. We should also recognize the role of adrenaline, a stress hormone that increases blood levels of free fatty acids and speaks to the potential for excessive stress to drive such problems here. Free fatty acids can easily be tested by most labs (best collected before breakfast).
ATP (adenosine triphosphate) is the energy currency of the human body and powers all energy-consuming reactions across all cells. ATP stores in each cells are continuously topped up by the mitochondria, the ‘powerhouses’ of the cell, although cells can also produce ATP via glycolysis (a ‘back-up’ pathway that is inefficient but can be useful to stem short-term deficits). Low ATP impacts a near-endless amount of cellular functions but is also has a rate-limiting effect on thyroid transporters that move thyroid hormones into the cell. From an evolutionary perspective, this makes perfect sense (as thyroid hormones activate energy-dependent enzymes, which could leave the cell drained if they were to act on a cell that already has low ATP). What’s more, in a cruel irony, it is also the case that low ATP is shown to reduce the function of the organic anion transporters at the kidney. Why is this relevant? Because this leaves the individual vulnerable to raised CMPF, indoxyl sulphate and hippuric acid (discussed above). In short, the mitochondrial function is always our starting point whenever we suspect cellular hypothyroidism. Mitochondrial performance is easily assessed with the Organic Acids test although there a number of more advanced testing options available.
- Takeways: there are identified metabolites and mechanisms that can be measured in assessing problems with thyroid uptake. While measurement can be highly useful, their primary use is in providing an understanding of the mechanistic relationships between energy status, dysbiosis, stress, obesity and liver/gallbladder health and sleep on cellular hypothyroidism. Mitochondrial activity remains the starting point in such investigations.
Making use of this mapping: translating theory to frontline
Recognizing the impact of these metabolites is important in clinic, not because we have to know their exact levels at each point of the journey but instead because it allows us to build clear mechanistic connections between the central metabolic patterns we are seeing and the persistence of hypothyroid symptoms in individuals who have normal thyroid labs. In short, if someone is subject to mitochondrial issues, insulin resistance, dysbiosis, anaemia, poor sleep or excessive stress, we should tread carefully when assessing their thyroid panel*. The need to do so is even more pronounced in individuals with kidney disease.
Clinical observation easily flags up most of these issues, although it is not hard to further characterize the exact metabolic picture with some basic initial testing. When working with individuals, I ask all to undertake an Organic Acids Test ahead of our initial appointment. This identifies hypoxia (determined by aconitic acid levels), many mitochondrial blockages, and the malic acid levels it measures are a key metric for cellular hypothyroidism. Add in a basic blood test to cover lipids and iron status, run basic HRV measurements then marry this up with the patterns we are observing, and we are left with a clear indication of the factors that impact on thyroid transport and therefore more fair view of cellular thyroid status (and when we should be highly cautious about allocating meaning into serum levels of TSH, T4 and T3) as well as initial steps we should be taking.
Testing HRV is simple, can be done with smartphones that most of us already own, and gives us a fantastic insight into the overall state of the system. It is highly correlated with the activity of the stress response, so too with inflammatory activity and also with insulin sensitivity. I see strong correlations between HRV and gut permeability (which can give rise to endotoxemia but also promotes formation of indoxyl sulphate in circulation). In short, if we make use of HRV measurements and conduct some thorough clinical screening, we can learn a lot about the most obvious obstacles (including cellular hypothyroidism) from a very modest amount of testing.
These ‘obvious’ obstacles are those that are going to need to be tackled and also obstacles that cast large shadows across the rest of the metabolism. For that reason, they stand out as our first step. Once such ‘obvious’ obstacles have been tended to, we can expect to either see the sort of resolutions we want or we can consider further testing to determine the cause of stalling (this is where we can consider direct testing of some of the markers above, but also stool tests and gut barrier functions to quantify endotoxemia issues, build a further picture on insulin signalling with fatty acid profiles, fasting insulin/free fatty acids and HbA1c, a repeat Organic Acids test, alongside other options that may vary depending on the individual picture). At which point, we inch closer to a point where we can begin to view thyroid blood tests in a different way, with increasing confidence that that reflect the cellular picture.
Such a process not only gives us the ability to yield lab results that actually mean something but, most importantly, it engineers a situation where both the body and the thyroid now have a fair chance to do their job. In other words, it engineers a situation where the individual is now ready to conduct healing, a process for which sufficient thyroid activity is non-negotiable, rather than simply run protocol after protocol with limited/absent results.
- Takeaways: mitochondrial disturbances, insulin sensitivity, excessive stress, iron dysregulation, endotoxemia and dysbiosis are factors that reliably create cellular hypothyroidism despite normal blood levels. Functional testing can identify which obstacles may be present in each individual and what course of action may be suitable.
Although the details involved in the management of cellular hypothyroidism can naturally be complex and are not all covered in this article (deiodinase enzymes and the conversion of T4 to T3, for example), I hope that I have successfully communicated how there are some fundamental principles that remain clear. Notably, as to the non-negotiable nature of thyroid activity in achieving any meaningful change, but also in regards to the inadequacy of outdated thyroid testing. Perhaps most of all, how decades of research (and my own 16 years on the frontline) make it clear that we need not be limited by dogmatic ways of doing things, and that we have a variety of options in both understanding what is actually going on and taking appropriate steps to resolve it.
*ps. It is worth noting that a complete thyroid panel (eg. TSH, Total T4, Free T3, Reverse T3, Anti-TPO and Anti-TG) may not tell us the level of cellular hypothyroidism in these circumstances but can still provide useful information in other areas, provided that thyroid transport activity is accounted for.