Thyroid Hormones and Prevention of Atherosclerotic Heart Disease: An Old-New Hypothesis (1994)

THYROID HORMONES AND PREVENTION OF ATHEROSCLEROTIC HEART DISEASE: AN OLD-NEW HYPOTHESIS ARYE LEV-RAN* Thyroid extract was the first potent hormonal preparation introduced into clinical medicine a century ago, when the words "endocrinology" and "hormone" were not yet part of the medical vocabulary. A couple of decades later, experimental atheromas were produced by feeding animals large doses of cholesterol, and because clinicians could measure serum cholesterol, the striking effects of thyroid hormone became known: in hypothyroidism serum cholesterol was almost always high, and it decreased dramatically when patients were treated with thyroid extract. At the other end of the clinical spectrum, hyperthyroidism was usually accompanied by low serum cholesterol levels that increased with successful treatment of the condition. Therefore, in the absence of specific hormonal assays of thyroid function, cholesterol determination took its place next to the basal metabolic rate (oxygen consumption) among the indirect diagnostic tests that only decades later were replaced by more specific hormonal measurements. Feeding animals cholesterol caused experimental hypercholesterolemia and atheromatosis, and high cholesterol was typical of clinical hypothyroidism ; thus it was logical to connect these observations and to suspect hypothyroidism as a possible pathogenetic factor in atherosclerosis in humans. Indeed, atherosclerosis of peripheral arteries was found to correlate with low protein-bound iodine and low basal metabolic rate, both pointing to hypothyroidism [I]. In the majority of patients who died of heart attacks, morphologic changes of the thyroid gland hinted at its deficiency [2]. The next logical step was to conduct a clinical trial with the thyroid extract (the only preparation then available). The dose of 2-3 grains of *Maccabi Sick Fund, Israel, and City of Hope National Medical Center, Duarte, California . Home address: 40/14, Yehuda Hanassi, Tel Aviv 69393, Israel.© 1994 by The University of Chicago. All rights reserved. 0031-5982/94/3704-0872$01.00 486 Arye-Lev Ran · Thyroid and Atherosclerosis desiccated thyroid (equivalent to 200-300 micrograms of thyroxine, about twice replacement) was given to elderly myxedematous patients with preexisting angina; it much more frequently decreased the pains than caused deterioration in the patients' conditions [3]. First experiments were carried out on hospitalized schizophrenic patients [4] and on healthy prisoners [5]. The hypocholesterolemic effect of thyroid extract was clearly evident in both groups. Soon promising results were obtained in general practice [6, 7]. In a large group of patients, encompassing 8,824 patient-years of observation, there were only four cases of new symptomatic coronary disease (all in males over the age of 55) instead of 72 cases expected in this age group. Serum cholesterol decreased in almost all patients to below 200 mg/dl. Moreover, thyroid extract doubled the ten-year survival rate in patients with a previous history of heart attacks. Decrease in serum cholesterol, in the frequency of angina pectoris, and in total mortality was reported a little later in another large group of subjects [8]. Enthusiasm for the use of thyroid hormone was tempered by the well-known clinical observations that patients with angina pectoris frequently experienced a sharp increase in pains when given physiological (replacement) doses of thyroid extract, especially when such therapy was started abruptly. Therefore it became standard clinical practice to start with low doses of the hormone and increase it cautiously. The use of thyroid hormone for prophylaxis of nonthyroidal disease in euthyroid individuals thus seemed potentially dangerous. At the time, researchers entertained the idea that synthetic d-thyroxine (not found in the body) might have advantages over the 1-thyroxine (the natural hormone) in decreasing serum cholesterol level without affecting myocardial oxygen demand. Now we know that this is not so and that d-thyroxine is simply a much weaker pharmacological equivalent of 1-thyroxine [9], but at the time the idea seemed logical. Several trials of d-thyroxine [10] demonstrated not only its hypocholesterolemic effect but other remarkable clinical properties: in patients with no history of angina, many fewer than expected developed myocardial infarctions; in those with preexisting heart disease, frequency of new coronary events or cardiac arrhythmias was not higher than expected, and these complications occurred mostly in the patients started abruptly with the dose of 4 mg d-thyroxine a day. Taken together, these observations...