Thyroid Hormone Effect and Metabolism – American Thyroid Association

Medscape & ATA Podcast Collaboration Presents: Growth Hormone and the Thyroid Gland: A Complex Relationship

ATA — Thu, 02 Jan 2025 16:15:07 +0000

The Thyroid Stimulating Podcast was created in partnership with the American Thyroid Association® and Medscape to discuss up-to-date diagnosis and management of a wide array of thyroid diseases. Listen to the newest podcast hosted by Kaniksha Desai, MD and Laurence Katznelson, MD: Growth Hormone and the Thyroid Gland: A Complex Relationship.

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Thyroid Health Blog: An Approach to the Patient with Thyroid Disease and High Symptom Burden

ATA — Fri, 15 Jan 2021 17:11:53 +0000

An Approach to the Patient with Thyroid Disease and High Symptom Burden

Benjamin Gigliotti, MD
University of Rochester Medical Center, NY
January 15, 2021

A common clinical dilemma is the management of patients with treated hypothyroidism and/or Hashimoto’s thyroiditis who feel unwell despite normal thyroid function tests. Weight gain, fatigue, brain fog, depressed mood, cold intolerance, constipation, dry skin, joint/muscle aches, hair loss, and brittle nails may be reported. These symptoms are commonly referred to as “thyroid symptoms,” and an internet search will reveal innumerable sources that reinforce a link between these and inadequate treatment or thyroid autoimmunity itself. However, clinicians must be cautious not to reflexively infer causation from correlation since:

– Even the most classic symptoms of hypothyroidism are non-specific and are commonly found in other diseases and in the general population.
– Anti-thyroid antibodies are often ordered in patients with unexplained symptoms, so autoimmune thyroid disease is disproportionately diagnosed in this setting; it remains unclear if this causes symptoms in and of itself.
– Most online resources emphasize the voices of people with thyroid disease who feel unwell since those who feel well do not tend to seek out or contribute to these resources.

In my experience, vague symptoms in this setting often have a multifactorial explanation, and thyroid disorders are rarely the dominant or only cause. Although the severity or number of symptoms can be daunting to evaluate, it is critical to meet the patient’s frustration with compassion, longitudinal relationship-building and thoughtful inquiry. Asking the following questions may prove helpful in determining the source(s) of symptoms:

-Is the normal TSH truly reflective of the patient’s thyroid axis?

Repeating the TSH over time can exclude spuriously or transiently normal results.
The upper limit of the TSH reference range (4-5mIU/L for most assays) is debated and may be lower in young patients or higher in older or obese patients. Regardless, I have never seen resolution of severe symptoms from treatment of a TSH that is within (or even slightly above or below) the reference range; several studies support this observation.(1)
Checking a free T4 level at least once can ensure concordance with the TSH and exclude assay interference (e.g. biotin or heterophile antibodies) or rare cases of central hypothyroidism).(2)
Total T3, free T3, and reverse T3 assays perform poorly in hypothyroidism and are rarely helpful, especially if the TSH and free T4 are normal

-Could there be an alternative explanation for each symptom that warrants workup, treatment, or counseling?

Weight gain and/or fatigue are particularly common, occurring in up to half of all adults. Inadequate or poor-quality sleep, excessive work, suboptimal diet, and inadequate exercise are common causes. Menopause can also contribute, especially if vasomotor symptoms disrupt sleep.
Hashimoto’s is associated with a higher rate of other clinically significant autoimmune diseases (e.g. lupus, rheumatoid arthritis, celiac disease) and numerous functional disorders (e.g. depression, migraines, irritable bowel syndrome, fibromyalgia).
Iron deficiency is common in menstruating women, a population enriched in autoimmune thyroid disease, and can cause a similar spectrum of symptoms, even without anemia or frankly low ferritin levels.

– Can thyroid hormone therapy be optimized?

Some patients on levothyroxine report improved symptoms after targeting a “low normal” TSH, although it is increasingly unclear if this approach is effective, and caution should be used in patients at risk for harm from iatrogenic hyperthyroidism.(3)
Many patients express interest in therapies other than standard-of-care levothyroxine (4); Dr. Shrestha recently wrote a thoughtful blog post on thyroid hormone formulations (https://www.thyroid.org/thyroid-prescription-levothyroxine/). It is prudent to consult with an experienced endocrinologist familiar with the literature and pros/cons of using T3 and T4+T3 combination therapy to determine their appropriateness on a case-by-case basis.

While there is rarely a panacea, engaging in supportive listening, initiating an appropriately comprehensive evaluation, setting realistic expectations, and seeking consultation with endocrinology (especially when questions about assay reliability or optimal thyroid hormone replacement arise) can prove beneficial.

References:
1. Biondi B 2013 The normal TSH reference range: what has changed in the last decade? J Clin Endocrinol Metab 98:3584-3587.
2. Burch HB 2019 Drug Effects on the Thyroid. N Engl J Med 381:749-761.
3. Samuels MH, Kolobova I, Niederhausen M, Janowsky JS, Schuff KG 2018 Effects of altering levothyroxine (L-T4) doses on quality of life, mood and cognition in L-T4 treated subjects. J Clin Endocrinol Metab. ePub 2018 Mar 2.
4. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, et al. 2014 Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid 24:1670-1751.

Disclaimer:
The ideas and opinions expressed on the ATA Blogs do not necessarily reflect those of the ATA. None of the information posted is intended as medical, legal, or business advice, or advice about reimbursement for health care services. The mention of any product, service, company, therapy or physician practice does not constitute an endorsement of any kind by ATA. ATA assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the material contained in, posted on, or linked to this site, or any errors or omissions.

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Thyroid Health Blog: Is Prescription Levothyroxine Really an Artificial Hormone?

ATA — Sun, 20 Dec 2020 03:39:25 +0000

Is Prescription Levothyroxine Really an Artificial Hormone?

Rupendra T. Shrestha, MD
University of Minnesota, Minneapolis, MN
December 20, 2020

Many patients try to avoid synthetic products and processed food as much as possible. This might imply that a hormone replacement considered natural is better. How do “natural” animal-derived thyroid hormone products differ from “synthetic” levothyroxine?

To understand this, we must understand some of the basics. The main hormone a thyroid gland produces is thyroxine – a molecule of tyrosine with four iodine bound to it. Thyroxine has left and right enantiomers – the same exact molecule rotated either to the left or to the right – levo- and dextro, respectively. Our bodies make thyroxine that is left rotated (or levothyroxine). The right rotated dextrothyroxine does not have any thyroid hormone action.

Levothyroxine brands and generics are all molecularly identical to levothyroxine — exactly the same molecule that the thyroid would be producing if it was to function normally! Therefore, if the manufactured compound is the exact compound that which we make naturally, is it synthetic or natural?

“Natural thyroid hormones” (such as Armour®, Nature-Throid®, or others) contain both levothyroxine and liothyronine. In these products, the levothyroxine is exactly the same as the synthetic versions, but the product is derived from a sheep or pig rather than from a machine. The liothyronine, or T3, is the more active form of thyroid hormone. Naturally, the thyroid produces a very small amount of T3. Most T3 is converted from T4 on an as-needed basis by various organs. Different organs require different amounts of T3 based on their metabolic state.

There are many people who do not get adequate symptom relief with levothyroxine and try animal thyroid extracts. These drugs are not approved by the FDA, and people who take them can end up overdosing thyroid hormone. This excess thyroid hormone is not without risks. Symptoms can include feeling warm, obtaining less sleep, and restlessness (which many perceive as increased energy). It also increases the risk of heart problems such as atrial fibrillation and can increase the risk of osteoporosis. Despite this, there may be some individuals who actually do benefit from T3. However, research has shown these patients are in the minority. Therefore, if taking animal thyroid extracts seem to give symptomatic improvement by giving higher dose of thyroid, it may come at a price.

If thyroid labs are normal on levothyroxine but a patient has persistent symptoms, one important step is to assess for other confounding problems such as sleep issues, lack of exercise and other chronic medical problems prior to considering a change in thyroid hormone.

In summary, while levothyroxine is made artificially, it is the exact molecule that our natural thyroid gland would have produced. On the other hand, the thyroid hormone extracts that are advertised as “natural products” are produced from the glands of animals, and the dosing is difficult to match to human requirements. Some patients may end up getting more hormone than is required and that can give a false sense of “improvement.” There may be some individuals who might benefit from additional T3, and more research is needed in this area.

For Further Reference:
American Thyroid Association Thyroid Hormone Treatment Brochure

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Research Grant to Identify the Source and Mechanism of Thyroid and Kidney Comorbidity Is Awarded to Nicholas Tardi, PhD, by the American Thyroid Association

ATA — Thu, 16 Aug 2018 21:33:02 +0000

Nicholas J. Tardi,Ph.D.
Rush University Medical Center
Chicago, IL Bio

The American Thyroid Association has awarded a 2018 Research Grant to Nicholas J. Tardi, PhD, Instructor in Internal Medicine at Rush University Medical Center in Chicago. Dr. Tardi’s project is titled “Deiodinase 3: A Thyroid Hormone-Associated Renoprotective Protein.”

The long-term goal of this project is to identify the source and mechanism of kidney and thyroid comorbidity. Thyroid hormone (TH) is a circulating, lipid-soluble molecule that plays an important physiological and developmental role in nearly all cells. Accordingly, precise control of TH activity is crucial to maintain metabolic homeostasis in several tissues.

Scientists have known for 30 years about the interplay between kidney disease and TH disorders, yet the underlying mechanism that links these two diseases has yet to be defined. Studying the effect of poor enzyme regulation of TH activity in the kidney may identify a causative disease mechanism. Dr. Tardi’s lab has previously shown that deiodinase 3 (D3), an enzyme that deactivates TH, is highly expressed in podocytes, which wrap around the capillaries of kidney filtration units and filter toxins from blood. This suggests that low TH activity is required for proper podocyte function. Mature podocytes cannot divide and cannot be replaced, so it is especially important that they continue to function properly. Unfortunately, they are a primary target of kidney disease. D3-deficient podocytes are more susceptible to injury, indicating that TH stability is important in preventing kidney disease.

Dr. Tardi’s laboratory will study the local effect of TH imbalance in both cell and mouse models to determine how D3 protects podocytes from injury. Additionally, they will define the prevalence of D3 misexpression in patients suffering from various kidney diseases. Identifying a local regulatory mechanism causing TH metabolism dysfunction will aid in developing targeted therapies to combat kidney and/or thyroid diseases that share a disease source.

Patients with hyperthyroidism show increased kidney filtration pressure and absorption capacity, while those with hypothyroidism show thickening of the glomerular basement membrane and reduced filtration rate. Despite the prevalence of overlapping complications of thyroid hormone disorders and kidney disease, a unifying mechanism regulating T₃ stability in the kidney is absent. Though well studied in endocrine tissues, the role of D3 in the regulation of thyroid hormone in renal tissue has not been addressed in the past. This study will use samples from clinical patients and representative disease models to define a therapeutic target.

Specifically, Dr. Tardi’s study will aim to:

Identify pathways associated with D3 dysfunction in podocytes: The laboratory will use microarray experiments to identify D3-responsive genes in podocytes and to screen potential activators and inactivators of D3. They will compare gene-expression profiles under healthy and injury-promoting conditions and set priorities to guide future studies of the signaling events that regulate D3 activity.
Establish the renoprotective mechanism of D3: The lab will use molecular biology-based experiments and morphological analysis to identify the mechanism by which D3 protects against podocyte injury. With confocal microscopy, they will examine cytoskeletal structure for hallmarks of podocyte injury. Protein analysis on known markers of podocyte health, metabolic processes, cellular stress, and protein trafficking will help to determine the mechanism of D3. They will correlate these cellular-level effects with the heavy proteinuria observed in D3-knockout mice models.
Define the prevalence of D3 misexpression in patients with kidney disease at single stages of its development: Dr. Tardi’s lab will analyze patient samples from the nephrology clinic at Rush University Medical Center to assess D3 as a potential biomarker for TH-associated kidney disease. They will use this data to develop studies targeting specific deiodinases to treat kidney disease. This is different from current therapeutic approaches that attempt to balance systemic TH levels to prevent the development of overlapping kidney disease.

Dr. Nicholas Tardi earned his PhD in Molecular and Cellular Biology in 2013 from Illinois State University, where he developed expertise in cell signaling, molecular mechanisms of disease, protein biology, and analytical processing to answer questions about cellular regulation of growth control pathways. Since joining Rush University, he has been investigating the molecular mechanisms of thyroid hormone imbalance in kidney disease and characterizing pharmacologically active agents to rescue kidney disease in mice. Recently, he has worked closely with two mentors to develop a niche to study kidney and thyroid comorbidity. Dr. Tardi’s passion for research, scientific expertise, and unusual technical perspective is reflected in publications in Nature Medicine, Science, Cell, and Genetics.

Dr. Antonio Di Cristofano, Chair, ATA Research Committee, says, “The ATA research grant program represents a unique and invaluable mechanism to foster the development of a new generation of basic, translational, and clinical researchers. Through this program, we allow these outstanding young scientists to test innovative hypotheses and generate preliminary data that will give them a significant competitive advantage when applying for traditional NIH-type funding.

This year we received 63 applications from 18 countries, spanning the whole spectrum of thyroid-related research. While, through a rigorous process, we have selected the most promising projects for funding, at the same time we regret we had to leave behind a number of excellent proposals. We are extremely thankful for the support we receive from members and organizations, including thyroid cancer survivors, which makes this outstanding program possible and allows the ATA to nurture the next generation of leaders in thyroidology.”

The American Thyroid Association (ATA) has awarded 99 thyroid research grants totaling over $2.8 million since the inception of the Research Fund. In addition, the ATA rigorously manages the selection of research projects and the distribution of over $1.8 million generously donated to the ATA specifically for research grants from: ThyCa, the Thyroid Cancer Survivors’ Association, Inc.; Bite Me Cancer; and the Thyroid Head and Neck Cancer Foundation.

The Thyroid Cancer Survivors’ Association, Inc. (ThyCa), has provided funding since 2003 in support of 72.5 special research grants totaling $2,084,375 focused on thyroid cancer and medullary thyroid cancer. In 2018 ThyCa is supporting half of a new medullary thyroid cancer grant with Bite Me Cancer, two new thyroid cancer research grants, and four renewing grants. ThyCa is a member of the ATA Alliance for Patient Education. Find out more at www.thyca.org.

Bite Me Cancer (BMC) is our newest grant funder, supporting 8.5 thyroid cancer grants since 2014 for a total of $201,250. BMC will be supporting a half of a new medullary thyroid cancer grant in 2018 with ThyCa and one renewing thyroid cancer grant. BMC is a member of the ATA Alliance for Patient Education. Find out more at www.bitemecancer.org.

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The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international, individual membership organization for over 1,700 clinicians and researchers from 43 countries around the world, representing a broad diversity of medical disciplines. It also serves the public, patients, and their families through education and awareness efforts.

Celebrating its 95th anniversary, ATA delivers its mission through several key endeavors: the publication of highly regarded monthly journals, Thyroid^®, Clinical Thyroidology^®, VideoEndocrinology, and Clinical Thyroidology for the Public; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators; support of online professional, public, and patient educational programs; and the development of guidelines for clinical management of thyroid disease.

Find out more about ATA at www.thyroid.org.

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Research Grant Focused on Identifying T3-Forming Sites in Thyroglobulin Is Awarded to Cintia Eliana Citterio, PhD, by the American Thyroid Association

ATA — Thu, 16 Aug 2018 21:31:24 +0000

Cintia Eliana Citterio, Ph.D.
Instituto de Inmunología, Genética y Metabolismo (INIGEM),
Universidad de Buenos Aires (UBA) –
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Buenos Aires, Argentina
Bio

The American Thyroid Association has awarded a 2018 Research Grant to Cintia Eliana Citterio, PhD, Assistant Professor of Genetics and Molecular Biology at the Instituto de Inmunología, Genética y Metabolismo (INIGEM), Universidad de Buenos Aires (UBA) – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Dr. Citterio’s project is called “De novo triiodothyronine (T₃) formation in T₃ toxicosis of Graves’ Disease.”

The project focuses on identifying T₃-forming sites in thyroglobulin (TG, the protein from which thyroid hormone is made) that are responsible for excess T₃ production in patients with autoimmune hyperthyroidism or Graves’ Disease (GD). The long-term objectives are:

To dissect the molecular mechanisms that underlie de novo T₃ synthesis in GD and in other thyroid conditions that are characterized by hyperactive thyroid TSH-receptors and preferential T₃ formation within thyroglobulin
To understand these mechanisms
To develop treatments that will repair them, if possible

Although thyroid hormone is perhaps the smallest chemical hormone known, the TG protein is a very large, complex molecule that has been very difficult to understand. Thyroid stimulating hormone (TSH) stimulates synthesis of the hormone by binding to a receptor (called TSH-receptor), which triggers many responses in the thyroid gland, including making more of the active thyroid hormone called T₃. For reasons yet to be discovered, the TG protein sometimes makes too much T₃, causing the anxiety, irritability, weight loss, enlargement of the thyroid gland, bulging eyes, and/or other symptoms that combine to indicate Graves’ Disease or related diseases.

Dr. Citterio proposes that, when TSH stimulates the thyroid gland, the TG protein structure is modified by a special enzyme that increases the ability of TG to make T₃. She has evidence that this special enzyme, named Fam20C, can add a phosphate residue at a particular site on the TG molecule, changing its structure. Increasing the amount of Fam20C in thyroid cells results in those cells making a TG protein that produces more T₃; inhibiting the enzyme results in less T₃ production. In GD, the stimulated thyroid gland makes more of the Fam20C enzyme; Dr. Citterio believes this is why patients end up with too much T₃ in their blood.

This project will attempt to find the specific location on the TG molecule where the extra T₃is released, which is likely from one of three sites. Using mutagenesis to eliminate each of those sites one at a time, Dr. Citterio will then test the TG protein to see whether it still makes more T₃ in cells that express more of the Fam20C enzyme, or in thyroid cells stimulated with a lot of TSH. The long-term objective is to understand, at a molecular level, why patients with Graves’ disease (and some other diseases) make too much T₃.

Dr. Citterio received her undergraduate degree from the UBA with a double major in biochemistry (Certificate of Honor) and pharmaceutical sciences. Her interest in thyroid function and disease began during her PhD research (completed in 2014, Summa Cum Laude) under the direction of Dr. Héctor M. Targovnik at the UBA. She has since published her research in 16 publications. In 2014, she was named a Fulbright Scholar to conduct postdoctoral studies in Dr. Peter Arvan’s lab at the University of Michigan, where she developed a new assay to measure de novo T₃ formation within thyroglobulin secreted from hyperstimulated thyrocytes (Citterio et al., 2017) and characterized the molecular mechanisms of T₃ formation at the antepenultimate tyrosine residue of thyroglobulin (Citterio et al., 2018).

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