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Critique of Thyroid Hormone Replacement Studies |
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Supporting
Documentation:
Four 2003
Studies Addenda
to: Addendum
1 In some statements, the researchers accurately reported what they found in their studies. In other statements, however, they quite inaccurately reported what they found. I’ve illustrated this below with specific excerpts.
However, they titled their published report with an invalid conclusion: "Combined thyroxine/liothyronine [T4/T3] treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone . . . ."[1,p.4543] (Italics mine, showing lack of proper qualification.) The title of their article will function as an advertising banner providing a memorable and quotable sound bite implying that no approach to T4/T3 therapy works better than T4 alone.
These accurate statements of Sawka et al., however, are buried within the text of their published paper. Precious few doctors, patients, or science reporters will ever read them. At the end of their abstract, however—which many doctors, patients, and reporters will read—Sawka et al. quite inaccurately wrote: "In conclusion, the current data do not support the routine use of combined T4 and T3 therapy in hypothyroid patients with depressive symptoms."[2,p.4551]
Addendum
2 Based on the studies showing that replacement therapies—including T4-replacement—are ineffective for many patients, the endocrinology researchers and other endocrinologists have recommended that T4-replacement remain the treatment of choice for most (Kaplan et al.[19,p.4541]) or all (Walsh et al.,[1,p.4549] Sawka et al.,[2,p.4555] and Clyde et al.[3]) hypothyroid patients. Below are the specific quotes. Walsh et al. wrote, "Unless beneficial effects of combined T4/T3 treatment over T4 alone can be convincingly demonstrated by others, T4 should remain the standard treatment for hypothyroidism."[1,p.4549] Sawka et al. wrote, ". . . there is insufficient evidence to support changing the current approach of routinely using T4 alone to maintain euthyroidism in hypothyroid individuals."[2,p.4555] Kaplan et al. wrote in their editorial concerning the Walsh and Sawka studies, ". . . evidence is fading that adding T3 to T4 is beneficial in the long-term treatment of hypothyroid patients with autoimmune thyroiditis . . . . We do not believe that the current evidence supports the use of T3 for these patients, who are probably the largest group of hypothyroid patients."[19,p.4541] Clyde et al. wrote, "This study supports these guidelines [of the American Association of Clinical Endocrinologists and the National Academy of Clinical Biochemists] by providing sound evidence that levothyroxine [T4] alone continues to be the most appropriate therapy for patients with primary hypothyroidism."[3] These endocrinologists, then, recommend that T4-replacement should remain the treatment of choice for hypothyroid patients. The four studies at issue, however, are an admission that T4-replacement is ineffective for many hypothyroid patients. None of the endocrinologists’ recommendations based on the studies, however, contain any allowance for the needs of these patients for symptom relief and preemption of potentially lethal pathology. This obvious disregard for these patients’ needs raises serious ethical and humanitarian concerns. Addendum
3 In the Clyde study, hypothyroid symptoms and/or their severity decreased about equally in patients treated with T4-replacement and those treated with T4/T3-replacement.[3] The improvement is inexplicable. It’s highly unlikely that the improvement was caused by T4-replacement. This is indicated by the fact that the patients, throughout the study, simply continued taking the dosage they’d been taking for at least six months before the study began. Cooper attributes the improvement to a placebo effect.[20] The replacement therapies, then, weren’t effective for the patients. Were it not for a placebo effect, natural variations in symptom intensity, or some unknown factor, the patients’ symptoms wouldn’t have improved at all. The outcome of the other three studies shows that replacement therapies weren’t effective for most or all patients studied. In the Cassio study, for example, the researchers treated infants who had congenital hypothyroidism with either T4- or T4/T3-replacement. Testing showed that regardless of the type of replacement used, hypothyroid infants had lower neuropsychological scores than did control infants who weren’t hypothyroid.[4] Replacement therapies, then, through their ineffectiveness, retarded the neuropsychological development in these infants. To take part in the Sawka study, patients had to have test evidence of depression. The researchers showed through their study that replacement therapies weren’t effective for these patients and left them depressed.[2] In the Walsh study, typical symptoms suffered by patients—despite their use of T4-replacement for at least six months—were "tiredness, impaired well-being, or weight gain." Patients’ test scores were "worse" for somatic symptoms, anxiety, and insomnia.[1] The study showed that replacement therapies were ineffective for these patients and left them suffering from their symptoms. Addendum
4 Endocrinologists warn of three potential adverse effects from dosages of thyroid hormone greater than replacement dosages: decreased bone density, acute adrenal crisis, and atrial fibrillation. Decreased Bone Density. Some eight years ago, I was surprised when bone density radiologists told me that a prevailing belief of endocrinologists was wrong: that TSH-suppressive dosages of thyroid hormone significantly reduce bone density. The available research literature confirmed that the radiologists were right. As they said, the evidence is that for most people, TSH-suppressive dosages of thyroid hormone don’t significantly reduce bone density or increase the risk for fractures. They were emphatic that there was no evidence that such dosages cause osteoporosis. Considerable evidence, however, shows that decreased bone density is not a likely adverse effect from TSH-suppressive dosages of thyroid hormone. Psychiatric researchers reported that "supraphysiologic" (TSH-suppressive) dosages of T4 for one year and longer didn’t significantly reduce bone mineral density in pre- or post-menopausal women with mood disorders.[32][33] Similarly, reviews of studies of thyroid cancer patients taking TSH-suppressive dosages of thyroid hormone show that the patients don’t have reduced bone mineral density; the studies included men and pre- and post-menopausal women.[17] But still, despite overwhelming evidence to the contrary, some endocrinologists today continue to issue their warning.[27][36] Acute Adrenal Crisis. Some endocrinologists also still warn that TSH-suppressive dosages of thyroid hormone may cause acute adrenal or Addisonian crisis, leaving a patient in shock and possibly dead. These warnings are based on a few published case reports.[80][81][82,p.872][83,p.813][85][86][87][88][89][90] For the most part, the cases involved patients in extraordinary circumstances. To extrapolate from these few reported cases to hypothyroid patients in general cannot be justified logically or scientifically. My colleagues and I have observed hundreds of hypothyroid patients whose impaired adrenocortical function was unveiled by thyroid hormone therapy, resulting in acute cortisol deficiencies. The worst symptoms most patients experienced were weakness and fatigue. We’ve not seen a single case of acute adrenal crisis. To protect patients from potential harm, of course, we should always err on the side of safety, especially with patients who have Graves’ disease.[82,p.872][83,p.813] But we err on the side of potential harm by keeping a patient’s dosage of thyroid hormone too low from fear of this extremely rare adverse effect. (See section above titled "Presumptions of the Endocrinology Specialty: Instability of Desiccated Thyroid, Dangers of T3, and the Safety and Effectiveness of T4-replacement.") Atrial Fibrillation. Today, the most often repeated warning against TSH-suppressive dosages of thyroid hormone involves the cardiac rhythmic disorder called atrial fibrillation. Researchers have conducted several studies and found that patients with the lowest TSH levels had an increased incidence of atrial fibrillation. The warning from the endocrinology specialty that has followed reports of this finding is that no patient taking thyroid hormone should have a suppressed TSH level. This warning, however, is based on an unjustified extrapolation from several studies. As Dr. Gina Honeyman-Lowe and I wrote in our 2003 book, Your Guide to Metabolic Health:
Other endocrinologists and medical writers have reported less than a three-fold increased risk of atrial fibrillation, but they also violate the rule of accurate scientific reporting by extrapolating from the specific study population to a population with distinct relevant differences. In a 2004 issue of the Annals of Internal Medicine, for example, Helfand wrote: "About one fourth of patients receiving L-thyroxine for primary hypothyroidism are maintained unintentionally on doses sufficient to cause an undetectable TSH level.[22][64] Data from the Framingham cohort suggest that 1 excess case of atrial fibrillation might occur for every 114 patients treated with doses of L-thyroxine sufficient to suppress TSH.[64]"[65] The implication of Helfand’s two sentences is that a suppressed TSH level from excess thyroid hormone predisposes patients to atrial fibrillation. However, some of the patients in the Framingham study may have had low TSH levels because of pituitary hypothyroidism. Among those patients, atrial fibrillation may have resulted from too little thyroid hormone rather than too much. Because of this, we can consider his calculation an unjustifiable inference from the Framingham study. In addition, Helfand failed to note that the people in the Framingham study were, as the authors of the study specified, "elderly," and they weren’t classified according to cardioprotective practices. His calculation, then, is illogical in that, as it’s written, it extrapolates from one class of people prone to cardiovascular disorders to all patients who have low TSH levels. Helfand’s statement constitutes inaccurate science reporting, and it is a disservice to the cause of scientific truth and quality patient care. (See section below titled, "Previous Atrial Fibrillation Studies: Possible Irrelevance to Hypothyroid Patients Taking TSH-Suppressive Dosages of Thyroid Hormone.") Patients With Heart-Protective Factors Not Studied. The endocrinologists’ warning of atrial fibrillation is unbalanced in terms of scientific evidence. In warning of atrial fibrillation, the specialists refer to no studies in which researchers controlled for factors known to increase resistance to atrial fibrillation. For example, in no studies have researchers controlled for heart-protective factors such as a non-atherogenic diet, cardiovascular exercise, or cardioprotective nutritional supplements. Studies must be conducted to assess any adverse cardiac effects of TSH-suppressive dosages of thyroid hormone in patients whose hearts are protected by these factors. On principle, whether individuals do or don’t avail themselves of these factors determines to a great degree their susceptibility to cardiac abnormalities such as atrial fibrillation. With a high degree of probability, the outcome of such studies will provide a more balanced view. Some hypothyroid patients with suppressed TSH levels are, of course, susceptible to atrial fibrillation. But cardioprotective factors render most patients more resistant to cardiac abnormalities. The incidence of atrial fibrillation with TSH-suppressive dosages of thyroid hormone will be strikingly lower than in people in general, and especially lower than in the sedentary elderly patients included in the previous studies. What’s needed is a study of a large population of people—both those protected by these factors and those not protected by them. If we include enough individuals, we’re likely to find a bell curve distribution of cardiac responsiveness to TSH-suppressive thyroid hormone dosages. On the right flange of the bell will be a diminishing percentage of people whose hearts are progressively more responsive to a particular TSH-suppressive dosage of thyroid hormone. Correspondingly, that diminishing percentage of people in the right flange will have a progressively higher susceptibility to cardiac abnormalities in response to that dosage. On the left flange of the bell would be a diminishing percentage of people whose hearts are progressively less responsive to the particular TSH-suppressive dosage. Correspondingly, that diminishing percentage of people in the left flange would exhibit a progressively lower incidence of cardiac abnormalities in response to the dosage. In other words, people on the right side of the curve would be progressively more susceptible to cardiac abnormalities, and those on the left would be progressively more resistant to abnormalities. The current method for establishing the reference range for the TSH and thyroid hormone levels ignores this mathematical and practical phenomenon dictated by the central limit theorem, which has accurately predicted anything and everything human beings have measured enough times in the past 270 years. To continue to ignore it—as do those who establish the reference ranges—is to doom practicing physicians to an unnecessarily high failure rate in the diagnosis and treatment of hypothyroid patients. From consideration of the central limit theorem, some diminishing percentage of hypothyroid patients clearly have some relative degree of tissue resistance to a particular dosage of thyroid hormone that most other patients are more responsive to. Normal metabolism in these patients is possible only with dosages of thyroid hormone that are overstimulating to most other patients. To deny them those dosages is to consign them to lifelong hypometabolism with all its attendant adverse health effects. This is truly inhumane. They are thusly consigned, however, when restricted to replacement dosages (which for them are clearly inadequate) to protect them from the atrial fibrillation that only patients on the right flange of the bell curve would experience. Previous Atrial Fibrillation Studies: Possible Irrelevance to Hypothyroid Patients Taking TSH-Suppressive Dosages of Thyroid Hormone. Aside from the bell curve phenomenon, a methodological issue may render the studies of atrial fibrillation irrelevant to patients taking TSH-suppressive dosages of thyroid hormone as a medication. The studies involved patients whose TSH levels were suppressed without the use of thyroid hormone. These patients, as a group, may differ in some relevant way from patients taking thyroid hormone from an external (exogenous) source. If they do differ in a relevant way, they may not share an increased risk of atrial fibrillation with patients who have endogenously suppressed TSH levels. I anticipate the criticism that this distinction isn’t important. My retort is that such distinctions are often made in defense of T4-replacement therapy. Recently, for example, Kaplan et al. noted that from using higher-end thyroid hormone dosages, thyroid cancer patients’ mood and cognitive dysfunction improved more than that of autoimmune thyroiditis patients.[19,p.4540] The cancer patients were taking higher dosages of thyroid hormone than the thyroiditis patients; in fact, about half of the cancer patients were using dosages that suppressed their TSH levels. As in other studies,[23][24][25][28][29][30][31][34] the thyroid cancer patients undoubtedly improved more because of their higher thyroid hormone dosages. Kaplan et al. conjectured, however, that thyroid cancer patients improved more—not because of their higher dosages of thyroid hormone—but because they differed in some relevant but undetermined way from autoimmune thyroiditis patients.[19,p.4540] Methodological issues remain relevant no matter who draws attention to them. Conclusion Regarding Warnings. Available scientific evidence shows that the endocrinology specialty’s sweeping warnings against TSH-suppressive dosages are unwarranted. Scrutiny of the evidence shows that the specialty has exaggerated the warnings in the extreme, and it has generalized them into invalid universal propositions. The specialty’s failure to show equal concern about the adverse effects of patients taking too little thyroid hormone suggests that its major concern is not protection of patients, but instead, perpetuation of the widespread practice of T4-replacement. Patient Safety Must Be Based on Evaluation of the Individual’s Tissue Responses to Thyroid Hormone. I want to emphasize that the responsiveness of different patients’ tissues to a particular dosage of thyroid hormone varies widely.[18,p.16] A particular dosage for some patients is overstimulating, while for others, it regulates metabolism perfectly—yet for still others, it is understimulating. In short, for any particular dosage of thyroid hormone, we’ll find a predictable bell curve of tissue responsiveness in the population, if we test enough subjects. In view of this, the only rational approach to safe and effective thyroid hormone therapy is a highly individualized one, based on how each patient’s tissues respond to a particular dosage. This cannot be accomplished by deductions based on levels of TSH or thyroid hormone, as the endocrinology specialty implies. The TSH level does change in response to changes in thyroid hormone dosage, but not within a range considered clinically relevant. In contrast, the resting metabolic rate, calculated from patients’ resting VO2 consumption, is a measure of tissue responsiveness that is highly sensitive to slight changes in thyroid hormone dosage.[79] Therefore, compared to the resting metabolic rate and other measures of tissue response, TSH levels are inferior as a method of fine-tuning thyroid hormone dosages. Addendum
5 Dr. James H. Hutton was the author of the 1966 book titled Practical Endocrinology. At that time, he was consulting endocrinologist at the Illinois Central Hospital. He had been professor of endocrinology at the Chicago Medical School, and past president of the Chicago Medical Society. Two physicians wrote introductory comments about Dr. Hutton in Practical Endocrinology. Dr. Ernest Olson wrote, "The author has been a consultant in endocrinology to the Illinois Central Hospital since 1920. It has been my privilege to observe the development of this specialty in our hospital since 1923 under his direction."[18,p.v] Dr. Chester Guy wrote, "The author’s long and rich experience in this field [endocrinology], together with his ability as a teacher, prompted the request that he prepare a series of lectures for the house staff of the hospital. These proved so interesting and practical that he was urged to incorporate them in book form under this appropriate title. It is believed that this volume, with its historical and humorous observations, and its directions for proven therapies, will merit a place in the libraries of those whose practices involve problems of the endocrine glands."[18,p.v] (Italics mine.) Introduction
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