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Symptomatic Hyperthyroidism in a Patient Taking the Dietary Supplement Tiratricol

      An 87-year-old woman was referred for evaluation of nervousness, tremor, insomnia, and fatigue of 2 months' duration. Initial laboratory evaluation revealed a suppressed thyrotropin level and an elevated triiodothyronine level. A review of her medications revealed that she had started taking several dietary supplements at the recommendation of her chiropractor before the onset of symptoms. One of these was tiratricol (3,5,3′-triiodothyroacetic acid or Triac), a substance sold as a dietary supplement despite classification as a drug by the Food and Drug Administration. Tiratricol has weak thyromimetic effects, can inhibit pituitary thyrotropin secretion, and in higher doses can significantly stimulate metabolism. Such was the case with this patient who presented with signs, symptoms, and biochemical evidence of hyperthyroidism that promptly resolved after discontinuation of tiratricol therapy. To our knowledge, this is the first reported case of documented thyrotoxicosis secondary to tiratricol use. Because tiratricol is still available for sale on several Internet sites, this case emphasizes the importance of inquiring about the use of dietary supplements in all patients. The availability of such products on the Internet increases the already complex task of monitoring patients' use of dietary supplements.
      FDA (Food and Drug Administration), T3 (triiodothyronine), T4 (thyroxine)
      The US public's fascination with dietary supplements shows little sign of abating. Sales figures for dietary supplements rose from $8.6 billion in 1994 to $13.9 billion by 1998.
      Good times roll in the nutrition industry.
      Although some of the currently available dietary supplements may have salutary effects, others may be not only unhelpful but can also result in severe toxic effects. Moreover, the loose definition of what constitutes a “dietary supplement” sometimes allows manufacturers to sell substances that would otherwise require a prescription and increases the chances for harm.

      REPORT OF A CASE

      An 87-year-old woman was referred for evaluation in May 2001. Complaints included nervousness, tremor, insomnia, weight loss, and fatigue of almost 2 months’ duration. She claimed good health until 2 months earlier when her chiropractor diagnosed “mild anemia.” At that time, several dietary supplements were recommended (Osteo-Genics, Hemagenics, Serenagen, Bio Pure Protein, Acida-Zyme, Therazyme, Ginkgo biloba, multivitamins, and tiratricol, 1000 µg, 3 tablets per day). The results of thyroid function tests performed 6 months before initiation of supplement therapy had been normal. At the time of her evaluation at Mayo Clinic, Rochester, Minn, the results of her examination, including thyroid palpation, were unremarkable. Thyroid function test results were abnormal (Figure 1, Table 1).
      Figure thumbnail gr1
      Figure 1Results of thyroid function tests in an 87-year-old woman.
      Table 1Patient Thyroid Function Test Results
      Reference ranges are 0.30 to 5.0 mIU/L for thyrotropin, 0.8 to 1.8 ng/dL for free thyroxine, 80 to 180 ng/dL for triiodothyronine, 25.0% to 39.0% for triiodothyronine uptake, and 4.2 to 12.0 μg/dL for total thyroxine. NA = not available.
      DateSensitive thyrotropin (mIU/L)Free thyroxine (ng/dL)Triiodothyronine (ng/dL)Triiodothyronine uptake (%)Total thyroxine (μg/dL)
      7/21/002.9NANA28.96.2
      5/1/010.0150.6293NANA
      5/29/015.90.898NANA
      * Reference ranges are 0.30 to 5.0 mIU/L for thyrotropin, 0.8 to 1.8 ng/dL for free thyroxine, 80 to 180 ng/dL for triiodothyronine, 25.0% to 39.0% for triiodothyronine uptake, and 4.2 to 12.0 μg/dL for total thyroxine. NA = not available.
      The patient was advised to discontinue use of all dietary supplements. When she returned for a follow-up evaluation 3 weeks later, she reported complete resolution of nervousness, insomnia, and fatigue, and thyroid function test results had returned to normal.
      The patient chose to restart the use of all supplements except the tiratricol. She returned 6 weeks later and reported feeling well with no recurrence of symptoms. Thyroid function test results remained in the normal range, supporting the diagnosis of exogenous thyrotoxicosis triggered by the ingestion of tiratricol.

      DISCUSSION

      Many patients (and some health professionals) consider dietary supplements to be “natural” and therefore safe. However, this case illustrates the potential for harm. Regulatory oversight of dietary supplements is limited, and even when the Food and Drug Administration (FDA) issues warnings about specific products, such products may continue to be available, especially on the Internet. Physicians who carefully (and nonjudgmentally) inquire about each patient's use of dietary supplements have an opportunity to educate and help patients make informed decisions. In the present case, recognition that tiratricol was the subject of FDA warnings allowed the consulting physician to counsel the patient to stop the use of tiratricol and prevent further adverse events.
      Tiratricol (3,5,3′-triiodothyroacetic acid or Triac) is a by-product of the metabolism of triiodothyronine (T3) and has been used as a thyroid hormone analogue.
      • Messier N
      • Langlois MF
      Triac regulation of transcription is T(3) receptor isoform- and response element-specific.
      • Asteria C
      • Rajanayagam O
      • Collingwood TN
      • et al.
      Prenatal diagnosis of thyroid hormone resistance.
      It has been used with some success as a prescription drug to suppress thyrotropin secretion in patients with nontumoral pituitary resistance to thyroid hormone.
      • Radetti G
      • Persani L
      • Molinaro G
      • et al.
      Clinical and hormonal outcome after two years of triiodothyroacetic acid treatment in a child with thyroid hormone resistance.
      • Beck-Peccoz P
      • Piscitelli G
      • Cattaneo MG
      • Faglia G
      Effectiveness of 3,5,3′-triiodothyroacetic acid (TRIAC), but not bromocriptine, in lowering TSH secretion in one hyperthyroid patient with non-neoplastic pituitary TSH hypersecretion [abstract].
      • Kunitake JM
      • Hartman N
      • Henson LC
      • et al.
      3,5,3′-triiodothyroacetic acid therapy for thyroid hormone resistance.
      More recently, it has been promoted as a dietary supplement to aid in weight loss. Because it is a naturally occurring substance and the definition of a dietary supplement is rather broad, manufacturers have used these loopholes to sell it directly to the public, usually as a “fat burner.” It also has become popular with bodybuilders as an aid to enhance muscle definition.
      The thyroid function test profile of our patient (elevated serum T3 levels, low serum free thyroxine [T4] levels, and a suppressed serum thyrotropin level) is compatible with so- called T3 thyrotoxicosis. Although tiratricol effectively suppresses thyrotropin levels (and subsequently T4 levels), symptoms of hypothyroidism do not typically occur, reflecting the intrinsic thyromimetic activity of tiratricol.
      • Kunitake JM
      • Hartman N
      • Henson LC
      • et al.
      3,5,3′-triiodothyroacetic acid therapy for thyroid hormone resistance.
      • Bracco D
      • Morin O
      • Schutz Y
      • Liang H
      • Jequier E
      • Burger AG
      Comparison of the metabolic and endocrine effects of 3,5,3′-triiodothyroacetic acid and thyroxine.
      Careful review of the composition of the other supplements failed to identify another agent that influences thyroid function. The failure of symptoms to reemerge after resumption of the other supplements also suggests that tiratricol was the offending agent.
      We considered the possibility that the elevated T3 level was spurious. It has been previously reported that most commercially available T3 radioimmunoassays significantly cross-react with tiratricol due to its structural similarity to T3.
      • Houlbert C
      • Houlbert D
      Interference of triiodothyroacetic acid in the radioimmunologic determination of triiodothyronine [letter] [in French].
      Therefore, our laboratory tested the cross- reactivity of 3,3',5-triiodothyropropionic acid (lot 34H5022, Sigma, St Louis, Mo) in our T3 assay and found a 33% cross-reactivity on a weight basis. Thus, part of the elevated level of T3 (293 ng/dL) could be accounted for by cross-reactivity. However, the suppressed thyrotropin concentration (0.015 mlU/L) and the clinically important symptoms support the contention that this patient was truly hyperthyroid. The low free T4 levels suggest that the excess levels of thyroid hormone were of exogenous rather than endogenous origin. The metabolic mechanism of the thyrotoxicosis is unknown, but it is likely due to a combination of tiratricol and T3 activity. Whether tiratricol activates thyroid receptors and/or suppresses pituitary secretion of thyrotropin is unknown. This issue was addressed in a recent American Thyroid Association press release:
      Overdosage of TRIAC can lead to symptoms of thyrotoxicosis, including but not limited to fatigue, rapid heart rate, weight loss, feeling hot, anxiety, and shakiness. At the doses recommended by the supplement's manufacturer, 2-4 1000 microgram capsules each day, many people will experience the same thyrotoxic side effects that they would develop if they consumed 100-200 micrograms of thyroxine. If blood tests are performed, the serum TSH [thyrotropin] and total T4 concentrations will be low; due to the suppression of pituitary-thyroid axis, while the serum total T3 level may be high, due to the cross-reactivity of T3 and TRIAC in most assays.
      There are 3 other published reports of adverse effects related to tiratricol. Ferner et al
      • Ferner RE
      • Burnett A
      • Rawlins MD
      Tri-iodothyroacetic acid abuse in a female body builder [letter].
      reported a case of a 29- year-old female bodybuilder who developed suppressed thyrotropin levels while taking a tiratricol product but who had no signs of thyrotoxicosis. Bentin et al
      • Bentin J
      • Desir D
      • Mockel J
      Triac (3,5,3′-triiodo-thyroacetic acid) induced “pseudohypothyroidism.”.
      documented 2 cases of pseudohypothyroidism secondary to tiratricol but again without signs or symptoms of thyrotoxicosis. Finally, Chow and Lam
      • Chow WS
      • Lam KS
      An overweight woman with galactorrhoea.
      reported a case of a 32-year-old woman who developed galactorrhea after initiation of tiratricol use. The presumed mechanism was secondary hypothyroidism exacerbating long-standing hyperprolactinemia. Thus, we believe ours is the first reported case of exogenous thyrotoxicosis triggered by ingestion of tiratricol.
      The FDA first issued a warning regarding tiratricol in 1999.
      • Food and Drug Administration
      This warning was in regard to a specific product (Triax Metabolic Accelerator) being marketed as a dietary supplement for weight loss. The FDA determined that tiratricol was in fact “not a dietary supplement but an unapproved new drug containing a potent thyroid hormone, which may cause serious health consequences.” The FDA had received reports of patients experiencing diarrhea, fatigue, lethargy, and/or profound weight loss.
      Four additional recalls also occurred. These included Tricana Metabolic Hormone Analogue (J.N.G. Sports Supplement Distributors, Bloomsburg, Pa), Tricana Metabolic Hormone Analogue (Thermo-Life International, San Carlos, Calif), Tria-Cutz, Thyroid Stimulator, Dietary Supplement Capsules (Gentech LLC, Edison, NJ), and Sci- Fi-Tri-Cuts Dietary Supplement Capsules (ATF Fitness Products Inc, Oakmont, Pa). Each of these products was reported to contain 1000 µg (1 mg) of tiratricol.
      Another warning was issued November 2000
      • Food and Drug Administration
      stating, “Despite four recalls over the past seven months, various products that contain tiratricol may still have reached consumers.” This was in part due to the fact that several distributors challenged the FDA's interpretation that tiratricol is a drug and continued to sell it as a dietary supplement. This highlights the difficulty the FDA has in regulating the realm of dietary supplements, in part due to the latitude granted manufacturers by the Dietary Supplement Health and Education Act of 1994. Faced also with the explosive growth of the Internet and the difficulties inherent in trying to regulate that medium, the FDA has been limited in its ability to police adequately all venues of sales of these products.
      Interestingly, a search of the World Wide Web performed on July 3, 2001, searching under the terms Triac and tiratricol, revealed several sites with products available for purchase that contain tiratricol. Thus, despite recognition of the potential seriousness of adverse effects with such substances, they remain readily available over the Internet. Most of the Web sites reviewed gave no indication of concerns or risks associated with use of the product. Claims included, “Never before has a fat burner worked as well and as safely … “ and “…if you are a healthy individual, Triac is perfectly safe for you.” (http://www.netrition.com/triax_article.html). Tiratricol was available at The MuscleShop (90 capsules for $59.99) with the claim “MOST EFFECTIVE fat burner/destroyer EVER developed” (http://www.muscleshop.net/TriCuts.htm).
      The wide availability of dietary supplements, both in retail stores and on the Internet, combined with the relatively loose regulatory environment that currently exists in the United States may pose serious risks. The classification of “dietary supplement” is a unique one, which “is specifically separate from ‘food’ or ‘drug’ categories, and as such, lies outside of the jurisdiction of many of the safety and regulatory rules that cover these categories.”
      • Bauer BA
      Herbal therapy: what a clinician needs to know to counsel patients effectively.
      With 71% of US households estimated to be using dietary supplements, physicians need to act as their patients’ advocates. By carefully inquiring into our patients’ use of dietary supplements, physicians can then educate patients about the risks and benefits of these dietary supplements. When adverse events occur, prompt reporting to the FDA MedWatch program (1-800-FDA-1088 or http://www.fda.gov/medwatch/index.html) increases the likelihood that definitive action can be taken to remove potentially dangerous substances from shelves, both real and virtual.

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