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History of Medicine |

The History and Future of Treatment of HypothyroidismThe History and Future of Treatment of Hypothyroidism

Elizabeth A. McAninch, MD; and Antonio C. Bianco, MD, PhD
[+] Article, Author, and Disclosure Information

From Rush University Medical Center, Chicago, Illinois.

Acknowledgment: The authors thank Dr. Martin Surks, Dr. Jorge Mestman, and Dr. Colum Gorman for providing additional historical insight for this project; they did not read or endorse the final text.

Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1799.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Requests for Single Reprints: Elizabeth A. McAninch, MD, Division of Endocrinology and Metabolism, Rush University Medical Center, 1735 West Harrison Street, Cohn Building, Room 312, Chicago, IL 60612; e-mail, Elizabeth_A_McAninch@Rush.edu.

Current Author Addresses: Dr. McAninch: Division of Endocrinology and Metabolism, Rush University Medical Center, 1735 West Harrison Street, Cohn Building, Room 312, Chicago, IL 60612.

Dr. Bianco: Division of Endocrinology and Metabolism, Rush University Medical Center, 1735 West Harrison Street, Cohn Building, Room 212, Chicago, IL 60612.

Author Contributions:Conception and design: E.A. McAninch, A.C. Bianco.

Analysis and interpretation of the data: E.A. McAninch, A.C. Bianco.

Drafting of the article: E.A. McAninch, A.C. Bianco.

Critical revision of the article for important intellectual content: E.A. McAninch, A.C. Bianco.

Final approval of the article: E.A. McAninch, A.C. Bianco.

Obtaining of funding: A.C. Bianco.

Collection and assembly of data: E.A. McAninch, A.C. Bianco.

Ann Intern Med. 2016;164(1):50-56. doi:10.7326/M15-1799
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This article has been corrected. The original version (PDF) is appended to this article as a Supplement.

Thyroid hormone replacement has been used for more than a century to treat hypothyroidism. Natural thyroid preparations (thyroid extract, desiccated thyroid, or thyroglobulin), which contain both thyroxine (T4) and triiodothyronine (T3), were the first pharmacologic treatments available and dominated the market for the better part of the 20th century. Dosages were adjusted to resolve symptoms and to normalize the basal metabolic rate and/or serum protein-bound iodine level, but thyrotoxic adverse effects were not uncommon. Two major developments in the 1970s led to a transition in clinical practice: 1) The development of the serum thyroid-stimulating hormone (TSH) radioimmunoassay led to the discovery that many patients were overtreated, resulting in a dramatic reduction in thyroid hormone replacement dosage, and 2) the identification of peripheral deiodinase-mediated T4-to-T3 conversion provided a physiologic means to justify l-thyroxine monotherapy, obviating concerns about inconsistencies with desiccated thyroid. Thereafter, l-thyroxine monotherapy at doses to normalize the serum TSH became the standard of care. Since then, a subgroup of thyroid hormone–treated patients with residual symptoms of hypothyroidism despite normalization of the serum TSH has been identified. This has brought into question the inability of l-thyroxine monotherapy to universally normalize serum T3 levels. New research suggests mechanisms for the inadequacies of l-thyroxine monotherapy and highlights the possible role for personalized medicine based on deiodinase polymorphisms. Understanding the historical events that affected clinical practice trends provides invaluable insight into formulation of an approach to help all patients achieve clinical and biochemical euthyroidism.


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Events influencing the evolution of treatment trends in hypothyroidism.

Initial strategies for thyroid hormone replacement included thyroid transplantation, but efficacious pharmacologic strategies soon won favor. Natural thyroid preparations containing T4 and T3, such as desiccated thyroid, thyroid extracts, or thyroglobulin, were the initial pharmacologic agents. Synthetic agents were synthesized later. Early clinical trials demonstrated the efficacy of synthetic and natural agents, but concerns arose regarding consistency of natural thyroid preparations and adverse effects associated with T3-containing preparations (natural or synthetic). With the demonstration of peripheral T4-to-T3 conversion and the availability of the serum TSH radioimmunoassay in the early 1970s, there was a major trend in prescribing preference toward l-thyroxine monotherapy. BMR = basal metabolic rate; DT = desiccated thyroid; IV = intravenous; RIA = radioimmunoassay; T3 = triiodothyronine; T4 = thyroxine; TG = thyroglobulin; TSH = thyroid-stimulating hormone.

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Dessicated thyroid tablets sometimes found in patients' stool
Posted on January 21, 2016
Joseph C. Meek, Justin B. Moore
Meek: Professor Emeritus, University of Kansas School of Medicine; Moore: Adjunct Associate Professor of Medicine, University of Kansas School of Medicine
Conflict of Interest: None Declared
In reading McAninch and Bianco’s account of Sidney Werner’s description of the shortened half-life of dessicated thyroid in humid weather (McAninch EA, Bianco AC. Ann Intern Med 2016 Jan 5;164(1):50-6, PMID: 26747302; Werner SC. The Thyroid: A Fundamental and Clinical Text. 3rd ed. New York: Harper & Row; 1971; 832-8.), we thought it appropriate to share a related story.

In the mid-1960s I (Meek) cared for a man with primary hypothyroidism. He was prescribed a reasonable dose of dessicated thyroid gland by mouth daily, which he reported taking faithfully. However, after several weeks he had not responded clinically to the treatment. A careful examination of his stool by Max S. Allen, MD, MACP, noted the presence of pristine, undigested tablets of dessicated thyroid. The patient was ordered to chew his thyroid tablets from that point forward, and he recovered uneventfully. The Internal Medicine service at the University of Kansas subsequently adopted a policy that all patients receiving thyroid hormone were to chew their dessicated thyroid, a policy that was undoubtedly despised given the metallic, malty taste of the medication.
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