NHS UKMi Q&A 56.5 (November 2011) TPA REBUTTAL
Thyroid Patient Advocacy (TPA) Response to UKMi Q & A (56.5) “What is the rationale for using a combination of levothyroxine and liothyronine (such as Armour Thyroid) to treat hypothyroidism?”
TPA finds that some of the statements made by UKMi are misleading, inadequate, and in parts, incorrect. TPA has provided additional relevant clinical information which we hope will be taken into consideration.
UKMi: Background – first sentence is misleading: levothyroxine (T4) is converted to triiodothyronine in peripheral tissues, providing stable and physiological quantities.
This should read levothyroxine (T4) is normally converted to triiodothyronine for correctness.
Although T4-only can partially mitigate symptoms for many, the results of a large UK study show that between 9% and 15% of patients prescribed T4-only continued to suffer symptoms that might, in some way, be related to their T4 only therapy. There are approximately 300,000 patients in the UK who do not benefit from this therapy. Peripheral thyroid hormone physiology exists and these patients should not be given a diagnosis of Hypothyroidism or treated with T4-only.[2-4]
Part of the problem lies with defects in the Royal College of Physicians (RCP) Teaching Curriculum, the GMC Endocrine Curriculum, and The Map of Medicine (MoM)  which give no guidance regarding recommended diagnostics and treatment of Euthyroid Hypometabolic Syndrome (EHM) despite the need for other thyroid hormones for some patients. Also, there are limitations to the interpretation of serum thyroid function testing. Taken together, these defects in the medical approach to symptoms of hypothyroidism cause an enormous disservice to patients who are placing their trust in the ability of the medical profession to properly apply what science tells us about thyroid physiology and biochemistry.
The UKMi pharmacists report is ONLY about those patients suffering with HYPOTHYROIDISM (under activity of the thyroid gland) which can, in most cases, be treated successfully with levothyroxine (T4) only. A logical examination of a continuing medical education course  and The Linguistic Etiologies of Thyroxine-resistant Hypothyroidism  find that the concepts of hypothyroidism and thyroid hormone therapy are unclear in current teaching and Medical Practice Guidelines. Pritchards peer-reviewed Paper ‘Reducing the Scope of Guidelines and Policy Statements in Hypothyroidism' exposes the above defects showing that endocrinology ignores those patients with deficient peripheral metabolism or increased peripheral hormone receptor resistance in their thyroid-only testing and therapy.
The RCP defines hypothyroidism as: The clinical consequences of insufficient secretion by the thyroid gland., which can, in most cases be successfully treated with levothyroxine-only. But, it states. In patients with suspected primary hypothyroidism there is no indication for the prescription of T4 or any preparation containing thyroid hormones to patients with thyroid blood tests initially within the normal range, which ignores the potential for euthyroid hypometabolism or other post-thyroid deficiencies. 
However, the broader and more helpful definition given by the British Thyroid Association (BTA) i.e. The clinical consequences of insufficient levels of thyroid hormones in the body”  includes not only the RCP definition, but also those with post thyroid deficiencies, i.e. euthyroid hypometabolism (EHMHM)[13,14] which are recognized by science. Unfortunately, the BTA does not maintain logical consistency with that definition because the association does not embrace post thyroid physiology, diagnostics or therapy. The two definitions for hypothyroidism were believed to be equivalent before 1950, but not after 1970 and the discovery of post thyroid physiology that can adversely affect thyroid hormone levels in the body, namely T3 levels that control the mitochondria.
UKMi: Background first paragraph, third sentence, is incorrect. Liothyronine (T3) has a much shorter half-life (1 day vs.6 days) and steady state levels cannot be maintained with once daily dosing.
UKMis demand for steady state levels of T3 may be misplaced since there are circadian variations. This issue is bogus because the variation is well within the normal range for T3.
This can ONLY be true if there are no post thyroid deficiencies. Unfortunately, post thyroid deficiencies are routinely ignored by Endocrinology, much to the dismay of all those victims of what amounts to medical negligence.
It is not possible to replace natural thyroid extract with synthetic T4 – only, as T4 is a pro-hormone and has little to no effect on its own. Natural thyroid extract contains not only T4, but the active thyroid hormones T3, T2, T1 plus calcitonin.
It is of great concern that a new study Levothyroxine and lung cancer in females; the importance of oxidative stress (published August 2013) shows that there is a correlation between lung cancer and levothyroxine treatment, and oxidative stress caused by T4 supplementation, can be one of the causes.
T4-monotherapy is inadequate for many. It is not an effective treatment for all patients and the UKMi Pharmacists should evaluate ALL available evidence regarding diagnostics and therapy, and the use of the active hormone T3 (either synthetic or natural thyroid extract), for those unable to regain optimal health on T4-monotherapy.[16-92]
The authors of the UKMi Q & A should read the Yellow Card reports that accompany the last 40 plus years of grossly under-reported adverse events on levothyroxine only. They will find no such data for Armour Thyroid, Erfa Thyroid, NatureThroid or Westhroid.
The Medicines and Health Care Regulatory Agency (MHRA} does allow doctors to prescribe the brands Armour Thyroid, Erfa Thyroid, Nature Throid, and Westhroid. These brands of natural thyroid extract are authorised by the FDA as medicines, and are standardised to the specifications of the USP. It is legal to prescribe any one of these brands to a patient in the UK and it can be delivered by UK pharmacies if there is a prescription from a licensed physician.[95,96]
Armour Thyroid, Erfa Thyroid, Nature Throid and Westhroid have never been required to be licensed in the UK. Armour and several other thyroid medications were ‘grandfathered’ in when Congress passed the Kefauver-Harris Drug Efficacy Amendments of 1962 to tighten control over drugs.[97,98] Before marketing a drug; manufacturers had to prove the safety and effectiveness for the product’s intended use. The requirement was applied retrospectively to 1938, when the Food, Drugs and Cosmetics Act was passed. Pre-1938 drugs were allowed because they were generally recognised as safe and effective, provided no evidence to the contrary developed. Too much evidence to the contrary developed concerning levothyroxine products and the FDA decided none was generally recognised as safe and effective, so these synthetic products lost their grandfathered privilege and had to go through the New Drugs Act (NDA) process. These four brands of NDT continue to retain their ‘grandfathered’ status since no evidence to the contrary has developed concerning their safe and effective status.
There is substantial evidence supporting the use of combination therapy, but conventional medical practitioners have made no attempt to evaluate the evidence regarding the use of natural thyroid hormone, and their wholesale dismissal of the concept represents, at least in part, a biased attitude. This biased attitude has been produced by the extensive evidence exclusion philosophy of Evidence-Based Medicine.
The MHRA Review of Unlicensed Medicines makes the point that: Clinicians should have the ability in appropriate circumstances to exercise their professional judgement to commission the supply of an unlicensed medicine to meet the special needs of an individual patient.
UKMi also appear to be ignoring substantial evidence [100-106] showing T4-alone does not work for ALL those suffering symptoms, and doctors have also reported patient dissatisfaction with T4-only therapy.[107-109] Kirk and Kvorning (1947) and Means (1954)  found that not all patients symptoms were mitigated with T4-only.
UKMi has also ignored the existence of numerous subsequent studies on the characteristics of peripheral conversion or metabolism of T4 to T3, and peripheral cellular hormone reception functions [16-92] These patients are NOT suffering with hypothyroidism and need a different diagnosis and therapy protocol. [14,15,109]
The view that hypothyroidism is best treated by T4-only is not, and never has been, based on solid scientific evidence. To this end, the effectiveness of whole thyroid extract versus synthetics should be compared in yet further clinical trials, especially involving problematic patients, as was first shown in a 2007 study comparing levothyroxine and desiccated thyroid extract in hypothyroid patients.
The following studies show that the UKMIs statement that no study has been found that specifically used the Armour Thyroid preparation (and by extension, similar desiccated thyroid products) is clearly FALSE.
There has recently been a new controlled trial, the results of which were published in the May 2013 Journal of Endocrinology by endocrinologists at the Walter Reed National Military Medical Center in Bethesda, Maryland.
There are 12 studies directly comparing natural desiccated thyroid extract to synthetic T4 and T4/T3 combination. Researchers have reported using Armour per se in 3 of these studies [112,114-116] and there are 9 published reports of direct comparison[117-125,] of the two forms of treatment i.e. natural thyroid extract and synthetic thyroxine. There are further studies establishing the clinical benefit of NDT. [126-147] and also reports of the therapeutic equivalence of NDT, T4 and T3. [148-150]
One study, in particular, was published in 1972. The researchers wrote, The present study was designed to compare the effects of desiccated thyroid and mono- sodium l-thyroxine [T4], administered by mouth, on serum lipids in a group of hypothyroid patients. The researchers reported, . . . a cholesterol-lowering effect was manifested by the time of first testing after institution of desiccated thyroid or l-thyroxine treatment. They wrote further, The magnitude of the hypolipidemic (fat lowering) effects, were similar when desiccated thyroid and l-thyroxine were give orally in therapeutic equivalent doses.,p.1047]
Another direct comparison was published in 1978. The researchers wrote, The biologic effect of the two therapies was compared by estimating by interpolation the dose of thyroid hormone that caused the peak serum TSH after TRH to fall to 5 U/ml.[115,p.1518] They concluded, . . . a daily dose of 100 mcg of T4 was on average equal in biologic activity to 100 mg of desiccated thyroid; 60 mg of desiccated thyroid was equal to 60 mcg of T4.[115,p.1518]
Two other research groups showed that the 60mg of desiccated thyroid had the effect of 100mcg of T4 in raising the basal metabolic rate.[147,149] A number of other researchers have made direct comparison of desiccated thyroid and T4.
The primary contention appears to be that if there are no, or not extensive formal trials between these different types of preparations, it is concluded that the synthetic preparations are more efficacious; Please note, there is NO validated published research showing that T4-monotherapy is safe and effective for all sufferers, therefore, the proposition by UKMi that levothyroxine-only therapy works for all patients suffering symptoms of hypothyroidism cannot, and must not be relied upon.
Alternative treatments to synthetic T4 and T3 are supported by decades of research and practice, and synthetic T3 and NDT must not be proscribed for patients with continuing symptoms of hypothyroidism on T4-only therapy. It is ONLY possible to use T4-only if there is no post thyroid deficiency and the peripheral conversion has sufficient extra capacity to handle the extra T4 needed to replace the thyroids production of T3.
The T4-only therapy ignores the need for T3 by those suffering from deficient post thyroid physiology. See The Greater Thyroid System Table.  This table illustrates the flow through this system starting at the top of the chart with signals from the brain to the bottom of the chart where the symptoms are sensed.
The goal of treating patients is mitigation of the symptoms of hypothyroidism, which may co-exist with being chemically euthyroid [13,14,154]
Medicine is quite capable of summarily dismissing evidence, as demonstrated by Sacket who wrote …and if no randomized trial has been carried out for our patients predicament, we must follow the trail to the next best external evidence and work from there,  and worse: If the study wasnt randomized, wed suggest that you stop reading it and go on to the next article. 
The studies found were flawed because:
- they used subjects that did not necessarily have post thyroid deficiencies and consequently had little need for T3,
- the T3-T4 therapies used generally had a lower therapeutic value than the T4 therapy they replaced,
- the analysis techniques used further reduced the impact of low-rate occurrences,
- the conclusion is not supported by the study, because the study did not cover all applications for T3, the methodology was unfair, and the analysis deficient. The recently published paper Reducing the Scope of Guidelines and Policy Statements in Hypothyroidism  takes apart the anti-T3 studies brick by brick. Those studies are about the thyroid gland only.
TPA, having the experience that accords with the test protocol Challenge/De-challenge/Re-challenge (CDR)  is collating a Register of Counterexamples and Triple Counterexamples to T4 Monotherapy, , which shows over 2440 counterexamples (15 October 2013). This Register records patients who continued to suffer symptoms on T4-only, yet found these symptoms were mitigated or remitted when they began T3 hormone therapy. The lack of counterexamples is the best evidence of good science.
The TPA Register has over double the number of participants in the studies showing that T4/T3 combination therapy worked no better than T4-only therapy (1216 participants)
The proscription of all T3-containing therapies has many such patient counterexamples. The evidence gathered by TPA alone indicates that Endocrinologys stance and continuance of T4-only treatment for all those with symptoms of hypothyroidism is without basis and is a pernicious practice causing harm to untold numbers of sufferers.
The Meta-analyses or reviews examine a facet of medicine. These reviews start by searching literature and examining selected literature for subject selection and continue with experimental methods, data analyses, and conclusion. All of these must logically support the current medical guidelines on hypothyroidism. THEY DO NOT.
Please compare the context and the authors conclusion in the abstract. The context is the continuing suffering by those being treated with T4. The conclusion is that T4 should be the only therapy for all sufferers. Is Endocrinology then content to let those, who continue to suffer symptoms onT4-only SUFFER?
The authors of the meta-analysis conclusion are then, understandable, after having summarily dismissed evidence using the EBM philosophy of excluding evidence. However, such dismissal does not comport with legal evidence exclusion. The dismissal of relevant literature and the studies scope, that is limited to the thyroid gland, renders the analysis and conclusions nonsensical.
An important factor in the design of studies is the choice of subjects, and the comparison. Since these studies are not representative of those with deficient peripheral metabolisms or increased peripheral hormone receptor resistance, THEY ARE DEFECTIVE.
The literature searches taken by three meta-analyses,[158-160] considered only 11, 9, and 9 studies respectively out of the 501 that were relevant. They rejected 490 of these studies. Thus, the investigations were reduced by 98% just because they were not done via RCTs.
Among the studies not considered were:
- Post-thyroid physiology [161-163]
- Warnings that T4-only therapy failed to mitigate the symptoms of hypothyroidism in some patients
- Verification of euthyroid hypometabolism, finding symptoms similar to hypothyroidism, and consequential production of patient counterexamples 
- Studies disagreeing with the meta-analyses conclusions [164,165]
- T3 being more active than T4, which suggests the meta-analyses examined a special situation, subjects whose post-thyroid physiology was not deficient; and
- Study and proper treatment of patients failed by endocrinology, finding symptoms similar to hypothyroidism, and consequential production of patient counterexamples.
The dismissal of applicable literature renders the analysis and conclusions of the meta-analyses so overstated they are false.
The focus on the thyroid gland suggests, in the literature, a 14 to 1 exchange because that is the ratio of T4 to T3 in the thyroid gland. Some studies used other ratios, such as 10:1 or 5:1. However, according to Celi, the relative therapeutic value is 3:1, indicating that those on the T4/T3 combination were under-treated. Furthermore, the T3 dosage levels were generally below the starting dose for adults. Moreover, the statistical averaging makes any improvement appear negligible.
These studies, which UKMi have used to back up statements in their Q&As report, should now be acknowledged as woefully deficient and discounted.
Armour Thyroid does have a higher amount of T3 compared to T4 than the relative amounts of T3 to T4 secreted by the human thyroid gland, however it is well documented that natural thyroid extract is often more effective and is better tolerated than synthetic preparations of T4, T3 and T4/T3 combination.[169,170] This is because the T3 in natural thyroid extract is absorbed more slowly than synthetic (purified, unbound) T3. It is also recommended that patients split their dose of NDT (and synthetic T3) into 2 or 3 doses daily to avoid such adverse reactions. Since T3 has a half-life or exponential decay, this can be mathematically analysed. This analysis shows that by taking T3 three times daily produces a variation far less than the normal range and potentially as low as the normal rhythms of the body. See Analysis 1- Exponential Decay 
The point of thyroidologists may be to titrate T4 until TSH is within the normal range. The point of medicine is to relieve patients of their adverse symptoms. This requires a deeper examination of physiology. The hypothalamus-pituitary-thyroid axis is nearly half of the relevant physiology. The remainder falls outside of the classical endocrine system and includes the:
- peripheral metabolism of T4 to T3,
- cellular hormone receptors for T3,
- T3 control of mitochondrial conversion of blood sugar and oxygen to water, carbon dioxide, and energy, and
- clearance of hormones into urine and faeces.
Unfortunately, this physiology does not offer as many tests. The measurements are serum T3 or free T3, hormones in the urine, the resting or basal use of oxygen, which indicates energy production, and resting or basal body temperature, preferably under controlled conditions. Without doing these tests, the healthcare professional has no idea why a patient has continuing symptoms when the thyroid tests are “normal.”
Also, by the logic that underpins the differential diagnostic protocol, these tests must be done to properly diagnose patients with continuing symptoms. In other words, endocrinology has been myopic in its diagnosis and treatment of the symptoms of hypothyroidism. This medical inadequacy is demonstrated by the numerous patient counterexamples whose lives have been virtually resurrected by addressing this additional physiology and replacing T3, its operative hormone,
A prominent endocrinologist claimed the following in a 2005 Food and Drug Administration meeting: T3 is the active ingredient, and its the thing that accounts for the thyroid hormone action. As Ive been reminded many times, there are no intracellular events that we know that can be described by T4 at the level of the nucleus. Only T3. T4 is not the active compound. Likewise, the site of action is in the nucleus.
Obviously, with the dismissal of post-thyroid assays, NHS healthcare professionals attempting to care for patients with continuing symptoms of hypothyroidism do not have sufficient information. It is sincerely hoped therefore, that UKMi Pharmacists will revise their Questions and Answers regarding What is the rationale for using a combination of levothyroxine and liothyronine (such as Armour Thyroid) to treat hypothyroidism? based on a careful reading of the original reports of the studies to which they refer and taking note of the findings described above. This lack of information makes the existence of counterexamples to T4-only therapy reasonable.
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