Measuring both the FT3 and FT4 serum level on all patients since l988, in both diagnostic screening and treatment-monitoring, has usually shown a large disparity between these two levels (unpublished data). Including T3 in the treatment (unless the patient had a life_threatening or cardiac-arrhythmic illness, in which a low T3 serum level may have been life_saving by keeping their metabolism and/or heart-rate low) invariably enabled patients to lose their classic hypothyroid symptoms, just as described in the literature (Dommisse, 1991 & 1993; Arem, 1999)) ~ something they had not been able to do with T4-only treatment, even when the FT4 level had been pushed to the maximum, or even beyond (Cooke et al, 1992). In most cases, it is important for both FT4 and FT3 levels to be optimized with whatever combination of T4 and T3 is necessary in treatment. This objective necessitated the use of both T3- as well as T4-containing preparations in the management of the vast majority of all hypothyroid patients. Gelenberg reported the same phenomenon in a psychiatric newsletter (1992). In 1997 IJ Chopra, contributor to some of the best papers and textbooks on thyroidology, published his paper on "The euthyroid sick syndrome: Is it a misnomer?" (Chopra, 1997). And, in early 1999, Leslie deGroot, another highly published thyroidologist, has published his own recent misgivings about the current dismissive approach to low free-T3 and -T4 serum levels in non-thyroidal illness/ euthyroid sick syndrome (DeGroot, 1999).
There are currently 4 categories of hypothyroidism that are often not being diagnosed as such, and therefore go untreated: (1) grade_3 primary; (2) subtle secondary/ pituitary without identifiable pituitary tumor or disease; (3) subtle tertiary/ hypothalamic in depression, chronic fatigue and other chronic illnesses; and (4) many cases of non-thyroidal illness/ 'euthyroid sick' syndrome in which the low FT3 (and sometimes even FT4) level is counter-productive and not life-saving. The remaining categories, grades 1 and 2 primary hypothyroidism, are very often undertreated.
Grades of Primary Hypothyroidism
A patient is considered to have grade-1 primary hypothyroidism when their serum FT4 level (and possibly the FT3 level) is below the normal range and the ultra-sensitive TSH is above its normal range . Grade-2 primary hypothyroidism is diagnosed when the FT4 and FT3 levels are in the lower half of their normal ranges but the sensitive TSH is elevated above its 'normal range' of approx. 0.5-4.2 mIU/L. Many physicians have also come to recognize a grade-3 hypothyroidism: Free-T4, Free-T3 and sensitive TSH all in their normal ranges but the TRH-stimulated TSH jumps up >20 points within 30 minutes. Since the advent of the ultra-sensitive TSH, it has been realized that the TRH-stimulation of the TSH is not necessary (Nicoloff & Lopresti, 1991), since it became apparent that a positive TRH-stimulated TSH test is equivalent to an ultra-sensitive basal-TSH in the higher part of its 'normal range', and signifies grade-3 hypothyroidism. Only about 5% of the physicians in the US treat grade-3 hypothyroidism and the authors are proud to count themselves among them because they have virtually never had a case that did not respond positively, in numerous ways, to their correction of that state. The current conventional approach appears to be tailor-made for many unpleasant surprises; just as one example, covert/ 'subclinical'/ grade-3 hypothyroidism can present initially as a myocardial infarction.
'Euthyroid-Sick'/ T3-Hypothyroidism
Another condition that is increasingly becoming regarded as not necessarily always free of thyroidal functional effects is the 'euthyroid-sick'/ non-thyroidal illness syndrome'. In this condition the FT3 level (and sometimes the total-T3 level or the FT4 level or Free Thyroxine Index ~ FTI/ T7) is below normal and the TSH is normal or even low-normal (Nicoloff & Lopresti, 1991). This is not due to pituitary or hypothalamic problems but due to other extrathyroidal illness. It is important not to over-treat this condition when it is present in acute cardio-arrhythmic or other severe potentially life-threatening illness because in these cases the low FT3 (or FT4 or FTI) may be potentially life-saving, by lowering the metabolic and/or cardiac rate. However, the majority of so-called 'euthyroid sick' cases these days appear to occur in chronic ambulatory conditions, such as fatigue or depression, in which the low FT3 level not only is not helpful but is actually harmful and is helping to perpetuate the fatigued or depressed state.
Also, psychiatrists have known for a long time that, even in the absence of diagnosed hypothyroidism, low T3 levels are actually causative factors in depression (Joffe, 1985). The depression is rendered refractory by this low T3 state and will frequently not respond to antidepressant medication unless T3 is used to augment the antidepressant medication. In bipolar-affective-disordered/ manic-depressive patients, leading psychiatrists have advocated and successfully used thyroid hormone treatment, especially supra-physiologic doses of T4, to help reduce the frequency and severity of the moodswings. In approximately one-sixth of individuals on lithium therapy, the thyroid function is lowered to a frankly-hypothyroid level (Barsano, 1991). There may be substantial numbers of other patients who should be considered to be rendered hypothyroid by this medication when a more-inclusive definition of hypothyroidism is used. So, many of the psychiatric cases who are regarded as euthyroid may in fact be cases of grade-3 primary hypothyroidism, secondary or tertiary hypothyroidism, or of 'euthyroid sick syndrome’ hypothyroidism. The term 'euthyroid sick' is now being openly disputed, meaning that the T3 used in augmenting antidepressant treatment may in fact be a 'back-door' entry to the thyroid treatment of refractorily-depressed hypothyroid patients (Cooke et al, 1992), until now regarded as euthyroid by the current approach to diagnosis.
The Current Standard and 'Alternative' Approaches
Two current popular reference texts on the thyroid and endocrinology Braverman & Utiger, 1991; Greenspan & Rappoport, 1991) point to the great functional importance of T3 thyroid hormone. It is 9 times more physiologically active, in comparison to the T4 hormone. The T4 hormone merely serves as a pro_hormone or pre-hormone, with the possible exception of brain-function, which may require a significant amount of T4 for its optimal function because T4 is transported through the choroid plexus and T3 is not (Whybrow, 1991; Whybrow, 1994). Despite this broad agreement on the roles of the two thyroid hormones, when it comes to diagnosis, these texts often only advocate the ultra-sensitive serum TSH level and, sometimes, a FT4 or a Free Thyroxine Index/ FTI/ T7 (but no FT3 level). And these experts recommend the sole use of T4 for treatment in nearly all cases. This paper will present evidence for the inclusion of the FT3 (and FT4) level in all thyroid screening and monitoring. It will also support the strategy of including T3 thyroid hormone, together with T4, in the treatment of most cases of primary, secondary, tertiary and non-thyroidal-illness hypothyroidism. This is implied by Escobar-Morreale et al with their discovery of the inadequate reversal of post-ablative hypothyroidism in rats by T4-only treatment (1996). If the TSH, FT4 and FT3 levels serve any diagnostic function at all, they do so only as an integral group of tests, each of which is in a reciprocal relationship to the others. The Escobar-Morreale study demonstrated that adding T3 to the replacement regimen did restore euthyroidism to rat tissues.
The major theoretical and practical reasons for the T4-only treatment-approach in the past centered around the greater stability of the T4 blood level, in comparison to the T3 level, which has wider diurnal and post_dose fluctuations (Chopra, 1991). The inaccuracy of the older tests for the T3 hormone also contributed to this perspective. However, the diurnal variation of T3 in the untreated human is fairly low; and twice_daily dosage of all treatment preparations containing T3 eliminates this objection in treated cases. Additionally, newer technology has provided the ready availability of the very accurate FT3 and FT4 blood levels (Stockigt, 1991). These factors have erased the validity of the current conventional approach. They have also removed the validity of the non-specific basal-temperature-recording 'alternative' diagnostic and monitoring method of Broda Barnes, as described in his 1976 book (Barnes, 1976).
The traditional, older tests of thyroid function, the serum total-T4, T3 uptake, free thyroxin index (FTI, also known as 'T7'), total-T3, and T3_by_RIA tests should be abandoned because they are inaccurate and unreliable as gauges of thyroid function (Stockigt, 1991). Physicians in Britain, South Africa and several other countries already did so, years ago. While the richest and 'most medically-advanced' nation in the world is adversely influencing people's thyroid health, in a penny-wise, pound-foolish way, by sticking to these cheaper, outdated, inaccurate tests ~ or limiting the blood-testing to a single, indirect, fallible measure of thyroid function, the ultrasensitive TSH test.
The most common conventional way to diagnose hypothyroidism is with an ultra-sensitive TSH that is elevated beyond the so-called 'normal reference range'. For most labs, this upper limit of the normal range is about 4.0 to 4.5 mU/L. This is thought to reflect the anterior pituitary's sensing of inadequate thyroid hormone levels in the blood or in its own cells, which would be consistent with grades 1 and 2 primary hypothyroidism. This will undoubtedly diagnose the severest grades of primary hypothyroidism, but it is far too limited a measure, and large numbers of patients who have some other form or degree of hypothyroidism will be missed. This strategy will fail to detect secondary and tertiary hypothyroidism because TSH is not elevated in these conditions; it will fail to detect the 'euthyroid sick' syndrome for the same reason; and it will miss grade-3 primary hypothyroidism because the 'normal range' for TSH has been set too high to identify this condition.
Two controversial 'alternative' physicians have also become associated with a focus on T3. The first was Dennis Wilson, MD, of Florida (1992). He noticed, in the early 90's, that many patients with chronic fatigue and other similar symptoms had low basal body temperature, a la Broda Barnes, and low T3 levels (actually low total-T3 levels, a less accurate depictor of the T3 status than the FT3 level). He dubbed this condition 'Wilson's Syndrome' (inappropriately-so because this name is readily confusable with Wilson's Disease, which is a disorder of copper metabolism named after a different physician, a long time ago). He treated them with a slightly-longer-acting form of T3-only, and said most of them improved significantly. He contended that, after a few months, the T3 could often be discontinued and some of the patients would not relapse into the low-T3 state, presumably because the supply of T3 had broken the 'vicious cycle' of the low T3 level that had caused a breakdown in the peripheral conversion of T4 to T3. [It is possible that the action of 5'deiodinase is dependent on a certain threshhold amount of T3.] Some patients, perhaps most, needed to stay on the T3 treatment. Other physicians find that these patients then have high-normal, above-normal, or way-above-normal FT3 levels, and subnormal or low-normal FT4 levels (unpublished data). This would be in a conventionally-treated hypothyroid patient, in which the FT4 level may be in or above the normal range but the FT3 level is at or below the low end of its normal range. We say 'almost as unfortunate' because, since T3 carries out 90% of the thyroid function (Chopra, 1991), having it at least adequate would appear to be more important than having T4 at an adequate serum level ~ if one has to choose between the two (which, of course, is not the case, if one thinks clearly about the matter).
The other physician promoting a controversial alternative approach to the management of T3-hypothyroidism is a chiropractor by the name of John R Lowe, of Texas. He has, particularly, found high doses of T3 very beneficial in cases of fibromyalgia (Lowe & Garrison, 1997). He has found that a substantial percentage of these cases is improved or put into remission by the correction of their low T3 serum level. He used T3-only preparations, similarly to Dennis Wilson, which produced analogous outcomes in the relative T3 and T4 serum hormone concentrations. His research-partner, Richard Garrison, is apparently currently engaged in a Veterans' Administration-approved study on the effects of T3 in Gulf War Syndrome, a condition thought to be related to chronic fatigue syndrome and fibromyalgia (which are, themselves, often present in the same patients). He is using hyaluronic acid, which has been found to be a marker for fibromyalgia (Yaron, 1997), as a gauge of the improvement, if any, brought about by T3 in Gulf War Syndrome.
A recent paper shows the superiority of T4+T3 over T4-only treatment of 33 hypothyroid patients in a double-blind crossover study (Bunevicius et al, 1999). The 4th author, Arthur Prange, is one of the several American psychiatrists who have published articles on the great benefit of T3 in refractorily depressed patients (Haggerty & Prange, 1990; Whybrow & Prange, 1981). It is likely that the benefit of the combination-approach in this paper would have been even greater if the FT3 and FT4 levels had both been optimized, rather than a fairly arbitrary amount of the previous T4 treatment simply being substituted by a functionally-equivalent amount of T3. However, this is a landmark paper that, together with those of Escobar-Morreale et al (1996), Chopra (1997), DeGroot (1999), and the present paper, as well as the popular book by one of us (Arem, 1999), will revolutionize the treatment of hypothyroidism, despite the cautionary editorial in the same issue of NEJM (Toft, 1999). Still further evidence of the shift toward including T3 in both the measuring and treating of the various forms of hypothyroidism is provided by yet another paper published during the closing stages of the writing of the present paper: The multi-center Italian 'Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism' has just reported that "both FT4 and FT3 serum levels ... are necessary for a more accurate disclosure of over- or under-treated patients." (Ferretti et al, 1999)
Some Modern Conventional Myths about Diagnosis and Treatment
In the author's opinion the current conventional approach is due to the following errors of thought: The first four concerns are widely-held myths that persist in the conventional medical community regarding the TSH and its role in the diagnosis and treatment of hypothyroidism:
(1)The first is that an elevated ultrasensitive_TSH level is almost-always required before a diagnosis of hypothyroidism can be made; and (2) that TSH's 'over-suppression' almost-always means that excessive treatment is in place. Normally, the anterior pituitary will secrete enough TSH to maintain adequate thyroid hormone levels. When this fails to occur, either grade-1-primary or secondary hypothyroidism is considered to be present. There seem to be subtle, conventionally called 'subclinical', failures of the anterior pituitary to produce sufficient TSH in response to low thyroid hormone levels that cannot be explained solely by the traditional form of secondary hypothyroidism (secondary to a pituitary tumor or outright pituitary failure, as in Sheehan's Syndrome: postpartum hemorrhage or infarction of the pituitary gland). This could also be due to a tertiary hypothyroidism (where the thyrotropin-releasing hormone ~ TRH ~ from the hypothalamus fails, for poorly-understood reasons, to stimulate the anterior pituitary to secrete adequate amounts of TSH), or to a TSH_specific hidden hypopituitarism.
(3) The third TSH-myth is that, just because the new ultrasenstive TSH test is a very sensitive and accurate test for measuring the TSH level, this suggests to imply that TSH is always or usually the correct yardstick by which to measure the function of the thyroid hormones, T4 and T3. There is an unconscious, unintentional 'sleight of hand' occurring here. The assumption is that, if TSH is low-normal, adequate amounts of T4 are being converted to T3 in the pituitary receptors; and that, if TSH is below normal, excessive amounts of T3 are being formed from T4 in those receptor cells. There does not appear to be any evidence that the pituitary gland ~ or any organ or tissue, for that matter ~ can convert T4 to T3 at any greater rate than that which is reflected in the serum FT3 level. Anyone who routinely measures the serum FT3 evel will observe that the serum FT3 level is often low, even when the TSH level is low-normal or below normal ~ even in the absence of identifiable pituitary or hypothalamic disease. Some of these cases are so-called 'euthyroid sick'/ non-thyroidal illness syndrome cases, some are subtle secondary or tertiary hypothyroid cases without known disease involvement of either the pituitary or the hypothalamus. And some are any combination of these two forms of hypothyroidism, or of non-thyroidal-illness hypothyroidism, or of grade-3 primary hypothyroidism.