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Critique of Thyroid Hormone Replacement Studies |
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FRF
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Current Study Four 2003 Studies of
Four studies published in late 2003 compared the effectiveness of two types of replacement therapy, T4 alone and combined T4 and T3 (T4/T3). In three of the studies,[1][2][3] patients who took part had been suffering from hypothyroid symptoms despite their T4-replacement therapy. The studies showed that neither form of replacement therapy improved the patients’ symptoms. In the fourth study,[4] researchers gave psychometric tests to hypothyroid infants after they had been on either T4- or T4/T3-replacement therapy for six and then twelve months. Compared to healthy infants, hypothyroid infants on both types of replacement therapy had impaired psychomotor function. In reporting this specific result of the studies—that neither type of replacement therapy effectively relieved patients’ symptoms or abnormal neuropsychological test results—three groups of people have misrepresented, perhaps inadvertently, the outcome: the endocrinology researchers who conducted the studies, the endocrinologists who commented on them, and the journalists who reported them. Rather than reporting the specific study result, these groups reported a false general conclusion: that no approach to T4/T3 therapy (replacement is the only one they tested) was more effective than T4 alone. This false general conclusion violates a rule of quality scientific reporting—that we precisely formulate our statements to accurately convey conclusions that we can validly deduce from the studies we report. Oddly, based on the negative outcome of these studies, some endocrinologists advise that T4-replacement should remain the treatment of choice for hypothyroid patients. Their advice, however, disregards two humanitarian imperatives:
 These imperatives require that the endocrinology specialty now impartially consider approaches to thyroid hormone therapy other than replacement. Alternate thyroid hormone therapies are already in demand and in widespread use by hypothyroid patients for whom T4-replacement is ineffective. These patients, many clinicians, and some researchers report that the alternate therapies are far more effective for the patients than replacement therapies. The endocrinology specialty’s objections to these other therapies have been either speculative or based on invalid conclusions from studies. This imposes an urgent scientific obligation on the endocrinology specialty: that it now open-mindedly reevaluate its objections to alternate thyroid hormone therapies. This is essential on both humanitarian and ethical grounds. In light of this obligation, endocrinology researchers must now cooperate in comparing the safety and effectiveness of replacement therapies to the alternate therapies. They must do this by reassessing without prejudice the already available historical, scientific, and clinical evidence; and by then conducting new, well-designed comparative studies. The endocrinology specialty faces a dilemma in considering a reassessment of its objections to alternate thyroid hormone therapies. It will find that it can best serve the welfare of hypothyroid patients for whom T4-replacement is ineffective by providing them with alternate thyroid hormone therapies. But, by providing other therapies for these patients, the specialty will risk losing financial support from the corporations that profit from its endorsement of T4-replacement. The result for the endocrinology specialty is that it will be compelled to show a steadfast commitment to scientific truth and patient welfare, or risk being deemed corrupt. In this critique, I explain my statements in this abstract. I also provide supporting evidence for my conclusions. False Reports of 2003 Study Results
and Potential Problems From Them
Based on the four studies, endocrinologists have advised that T4-replacement should remain the treatment of choice for hypothyroid patients. Their reason is that T4/T3-replacement worked no better than T4-replacement. This advice is foreboding for patients who remain symptomatic on T4-replacement, for the four studies are a concession of endocrinology researchers that the therapy leaves many patients suffering. For these patients’ welfare, endocrinologists are obligated to reassess their advice in view of its predictable pernicious consequences for the patients. I explain this in the section below titled "Dilemma for the Endocrinology Specialty." First, however, I’ll point out an invalid conclusion endocrinologists stated in their reports of the study results. Patients, physicians, reporters, and the endocrinologists themselves must understand the invalidity of the conclusion; otherwise, they are likely to promulgate a false belief about the results of the studies. Valid and Invalid Conclusions of the Endocrinology
This invalid conclusion is a linguistic reformulation of the valid one. I’ll explain this in the lexicon of the logician. The endocrinologists deduced from the studies a valid existential (specific) proposition: Neither T4-replacement nor T4/T3-replacement improved patients’ hypothyroid symptoms. Then, they reformulated that proposition into an invalid universal (all-inclusive) proposition: No approach to T4/T3 therapy is more effective than T4 alone in relieving patients’ hypothyroid symptoms. These differently formulated conclusions have entirely different meanings. The difference is the same as researchers first saying, "Our study showed that as race horses, short stallions are no more effective than short mares," and then concluding, ". . . as race horses, stallions are no more effective than mares." The first statement refers to a specific class of stallions and mares—short ones; the second refers to all stallions and all mares, despite their height. In that the researchers studied only short stallions and mares—not all stallions and mares—they cannot validly deduce their second proposition from the first. To do so is a flagrant non sequitur. The endocrinologists who performed these studies committed exactly the same logical error and reported an equally flagrant non sequitur. They cannot validly deduce from the results of the four studies that no T4/T3 therapy works any better than T4 alone; yet this is precisely the meaning of their universal conclusion (and the implication of the titles of all four study reports).[1][2][3][4] The endocrinologists may have reformulated their valid conclusion into an invalid one inadvertently. But that doesn’t change the fact that their doing so violates a rule of quality scientific reporting—that we precisely formulate our statements to accurately convey only the valid conclusions deducible from study results. In Addendum 1, I’ve excerpted statements from the endocrinologists’ published reports of the studies. The excerpts show that each of the published reports contains both valid and invalid conclusions. In response to my distinction between the valid and invalid conclusions, I predict a particular protest: I’m quibbling; what I’m referring to as an invalid conclusion is only a version of the conclusion abridged to be wieldy and understandable—an abridgment demanded by journal and newspaper editors. But to abridge is to shorten while maintaining the basic meaning—not to convert a valid specific statement into an invalid universal one. It is understandable that reporters and editors of newspapers and newsletters sometimes fail to accurately report conclusions from studies. Most aren’t practicing researchers, and we can excuse them for occasionally lacking the precision expected of researchers. To understand their imprecision, however, is not to condone it; we should implore them to accurately report the results of scientific studies. In this case, however, reporters and editors are only parroting an invalid conclusion from the researchers themselves. Endocrinologists have perpetuated other invalid and false conclusions (see section below titled "Potential Harm from TSH-Suppressive Dosages of Thyroid Hormone") that reporters have parroted. It would be inexcusable, however, to have to add to the list the invalid conclusion now at issue. Few physicians, patients, or reporters will read the full-text reports of the four studies. Instead, they’ll read only the brief invalid conclusion of the researchers in various publications. Some will read only the abstracts of the four reports in PubMed. As a result, it’s likely that they’ll falsely believe the researchers found that no approach to T4/T3 therapy is more effective than T4 alone. Already in JAMA, we see the title of an article, "Combined T4 and T3 Therapy—Back to the Drawing Board."[20] In that this title is not properly qualified, many doctors, fast-moving by necessity, will read only the headline, and their belief system will inaccurately echo it. No more Armour or Thyrolar for their patients! After all, the doctors have an ethical obligation to go where science points. Armour and Thyrolar contain T4 and T3. The studies show that these are no more effective than T4 alone, so the doctors must prescribe T4 alone, as the researchers advise. Few reporters who read the researchers’ full reports or abstracts of them are likely to announce to their readers what the researchers actually found. Instead, they’ll quote or rephrase what they read in the reports or abstracts—the invalid conclusion. To illustrate, the invalid conclusion of the endocrinology researchers and commentators was the headline of a news article at a popular website, docguide.com: "Combination Levothyroxine/Liothyronine [T4/T3] Shows No Obvious Benefit Over Levothyroxine [T4] Alone in Patients With Primary Hypothyroidism." The first sentence of the article echoed the title: "Patients who are treated with a combination of levothyroxine plus liothyronine for primary hypothyroidism gained no apparent benefit compared with patients treated with levothyroxine monotherapy, say researchers."[21] The headline alone is certain to mislead readers who stop there. The intention of the reporter, Joene Hendry, most likely was not to mislead. But in abbreviating the studies’ conclusion, that is exactly, though inadvertently, what she did. Hence, a false belief about T4/T3 therapies has already been engendered by endocrinologists’ violation of this rule of quality science reporting. Researchers, physicians, patients, and reporters should exhort the endocrinologists to practice the same precision that we implore reporters to practice. Whether the endocrinologists heed the exhortation is a matter of scientific integrity. Endocrinologists’
Odd Treatment Advice for
Patients Who This is the equivalent of researchers taking people who suffer from thirst when restricted to one glass of water per day; letting them try as an alternative one glass of mixed water and tea; seeing that the one-glass mixture relieves thirst no better than one glass of water; and then, based on this outcome, advising that these people continue to drink one glass of water per day. The one glass of water left the people thirsty before the study, and failure of the one-glass mixture to relieve their thirst doesn’t mean one glass of water alone will now do any better than before. Similarly, many hypothyroid patients have continuing symptoms on T4-replacement, and the failure of T4/T3-replacement to relieve their symptoms doesn’t mean that now T4-replacement will. As the endocrinologists imply, T4-replacement (and T4/T3-replacement, which they discourage) will indeed work well for some hypothyroid patients. For others, however, replacement therapies are clearly ineffective. The studies are in fact "a randomized double-blind" admission by the endocrinology researchers that T4-replacement is not effective for many patients. (See Addendum 3 for evidence of persisting symptoms of hypothyroid patients in the studies despite their use of T4-replacement.) Despite this, none of the endocrinologists have noted an ethical and humanitarian responsibility made clear by these studies: to provide patients for whom replacement therapies aren’t effective with alternate thyroid hormone therapies that are safe and effective for them. This responsibility is made even clearer by several other studies. These studies indicate that patients on T4-replacement have an increased incidence of potentially fatal diseases, and increased chronic use of medications for these diseases (see section below titled "Presumptions of the Endocrinology Specialty: Instability of Desiccated Thyroid, Dangers of T3, and the Safety and Effectiveness of T4-replacement"). The endocrinologists’ failure to note this responsibility suggests a cavalier disregard for the needs of patients who remain symptomatic and susceptible to pathology on T4-replacement therapy. The only humane option for the endocrinology specialty is to now open-mindedly reconsider thyroid hormone therapies other than replacement, including TSH-suppressive therapies. Alternate Approaches to Thyroid Hormone Therapy The most effective of these therapies involves adjusting patients’ dosages of combined T4/T3 or T3 alone according to several indices other than TSH and thyroid hormone levels. Those indices are signs, symptoms, and various objective measures of tissue response to particular dosages. When patients’ dosages are titrated according to these indices, dosages that prove safe and effective are typically TSH-suppressive.[44] Evidence is available that this therapeutic approach relieves patients’ signs, symptoms, and measurable tissue abnormalities such as low resting metabolic rates (RMR) according to indirect calorimetry. In the studies at issue, endocrinologists used thyroid function test results as the exclusive criteria by which to titrate patients’ thyroid hormone dosages. Despite denials,[26] this is precisely the method used by endocrinologists at large to titrate patients’ dosages. This method (which I termed "extremist medical technocracy" in The Metabolic of Treatment Fibromyalgia[44]) varies from that of the clinician using the protocol I describe here. This clinician uses thyroid function test results as an aid to clinical judgment—an aid that is integrated with other aids, such as objective measures of tissue response to thyroid hormone. Thyroid function test results help this clinician form an opinion as to the patient’s pre-treatment thyroid status. After he establishes the patient’s thyroid status, however, he seldom uses thyroid function test results to reach treatment decisions. His reason for not using them to titrate dosage is that most of his patients have previously failed to benefit from T4- or T4/T3-replacement therapies, in which, of course, physicians adjusted dosages according to the patients’ TSH and/or thyroid hormone levels. Only by this clinician not using the replacement method for titrating dosage are most of these patients able to recover from their symptoms, signs, and objective measures of tissue hypometabolism. The fact that so many patients have recovered from their symptoms, signs, and tissue abnormalities with this alternative to replacement therapies compels a proposition: T4-replacement therapy previously impeded these patients from recovering their health. It becomes imperative, then, for the health and welfare of such patients that practitioners
Despite this clear-cut imperative, Kaplan et al., in their editorial comments on the four studies, stipulated that in future studies, "TSH should be monitored dynamically and study medications adjusted according to the results, to maintain normal serum TSH concentrations."[19,p.4541] To make this recommendation, Kaplan et al. had to ignore the major finding of the four studies: that replacement therapies—in which clinicians adjust patients’ dosages to maintain reference range TSH levels—are ineffective for many hypothyroid patients (and specifically for most patients in the four studies), leaving them to suffer from hypothyroid symptoms. In their editorial, Kaplan et al. also appear to ignore a telling observation of their own: in one study, 15 thyroid cancer patients used TSH-suppressive dosages of thyroid hormone; their mood and cognitive function improved more than those of patients with autoimmune thyroiditis who used replacement dosages.[19,p.4540] This observation suggests that dosages higher than those dictated by the replacement concept more effectively relieve patients’ hypothyroid symptoms. Other research has shown that patients report feeling better with TSH-suppressive dosages of thyroid hormone.[23][24][25] Moreover, psychiatrists report that dosages of T3 higher than replacement dosages augment the depression-relieving effects of antidepressants.[9][28][29][30][31][34] In addition, in a study of patients made hypothyroid by therapeutic destruction of the thyroid gland, some used TSH-suppressive dosages of thyroid hormone and others used T4-replacement. Those on TSH-suppressive dosages didn’t gain excess weight; those on T4-replacement did. The researchers concluded that T4-replacement was the cause of the excess weight gain.[55] These published reports are consistent with thousands of cases in which hypothyroid patients recovered from their symptoms and other health problems with TSH-suppressive dosages of thyroid hormone after T4-replacement failed to help them. Kaplan’s observation also suggests another point: that T4-replacement keeps many hypothyroid patients’ dosages too low to relieve their symptoms is an indictment of the concept of replacement. As the cause of
T4-replacement constitutes a public health menace—one responsible for colossal human suffering and huge financial burden to society. In view of this circumstance, the advice of Kaplan et al. appears to be indefensible. It also appears, based on the outcome of the four studies, that the endocrinology specialty now has an ethical and humanitarian obligation to challenge the veracity of its own presumptions about the safety and effectiveness of replacement therapies. (See section below titled "Presumptions of the Endocrinology Specialty: Instability of Desiccated Thyroid, Dangers of T3, and the Safety and Effectiveness of T4-replacement.") As I wrote above, alternate thyroid hormone therapies are already in widespread use, and physicians and patients who use them contend that treatment results are superior to those of T4-replacement. These reports, in light of the outcome of the four studies, should impel anyone even mildly charitable toward patients who suffer while on T4-replacement, to advocate studies comparing T4-replacement with alternate thyroid hormone therapies. Patient Safety In Addendum 4, I provide a brief summary of each of these putative adverse effects. Each is either speculative, never shown to be clinically significant, or based on invalid deductions from studies. The specialty has argued that T4-replacement therapy is superior to other approaches to thyroid hormone therapy because it enables patients’ TSH and thyroid hormone levels to remain stably within their reference ranges. The idea that stability within the reference ranges is vital to the safety of all patients, however, is a presumption. Studies show that keeping these hormones within their reference ranges harms many patients in three ways: it perpetuates their hypothyroid symptoms, increases the incidence of potentially fatal diseases, and increases patients’ regular use of drugs to control their hypothyroid symptoms and the other diseases. Introduction
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