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.

The post Thyroid Health Blog: An Approach to the Patient with Thyroid Disease and High Symptom Burden appeared first on American Thyroid Association.

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

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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Sarah Oltmann, MD
University of Texas Southwestern, Dallas, TX
November 16, 2020

November marks hyperthyroidism awareness month, so what a fitting topic to discuss for our Thyroid Health Blog!

It is important to remember that hyperthyroidism can occur at any age. While most may present with a rather typical constellation of symptoms, many may present with exacerbation of pre-existing conditions which may make the diagnosis initially elusive. Worsening anxiety, insomnia, fatigue, panic attacks, palpitations, hypertension or diarrhea may not initially signal that the thyroid is involved. Clinicians must have a low threshold to check thyroid function early to rule out a component of hyperthyroidism.

Once a suppressed thyrotropin (TSH) has been detected, further investigation with serum triiodothyronine (T3) and free thyroxine (free T4) can help delineate overt from subclinical disease. A thorough history of past thyroid disease, as well as current medications and supplements, can help detect any pre-existing diagnoses or exogenous sources of thyroid hormone or over supplementation with iodine. More commonly, hyperthyroidism is due to either Graves disease, toxic multinodular goiter or toxic adenoma. Distinction between these can usually be made with the assistance of a thyroid uptake scan, TSH receptor antibody measurement, and thyroid ultrasound. An additional physical exam finding of exophthalmos can further support the diagnosis of Graves’ disease. Understanding the etiology can help guide patient expectations. A small percentage of patients with Graves’ Disease may undergo spontaneous remission after 1 to 2 years, which may prompt patients to wait before considering a definitive treatment option.

With confirmation of the diagnosis of hyperthyroidism, focus is on hormonal control with an antithyroid medication (ATM, most commonly Methimazole in the United States). This may be augmented with beta-blockade, steroids, cholestyramine or SSKI for those who are difficult to control.

Many patients may need further consideration for definitive management with either radioactive iodine ablation (RAI) or thyroidectomy. Your local resources may also influence these options, but it is critical to understand that all three treatments (ATM, RAI and thyroidectomy) are possible options. Certain patient factors and priorities may alter the preferred definitive treatment. Smaller gland size, easy to control hormones, and lack of eye symptoms are factors that may favor continued ATM management. A large goiter with compressive symptoms, difficult to control hormones requiring high dose medications/ multiple modalities, pregnancy, severe eye disease, multiple nodules within the thyroid with or without thyroid cancer, or desire for rapid and reliable hormone control may favor thyroidectomy. RAI is a good option for patients with a smaller gland size, and a desire to pursue definitive management but avoid surgery.

There are also relative contraindications for treatment options. ATMs may have serious side effects, like agranulocytosis or liver failure, which prevent further use, or may cause skin eruptions making long term use intolerable. Additionally, high dose requirements or fluctuating doses may make long term use of ATMs not reliable. Women who are pregnant, wanting to become pregnant in the next 6 months to 1 year, breast feeding or have small children in the home will want to avoid RAI. Patients with severe eye involvement, have a large goiter with compressive symptoms, or are smokers should also avoid RAI. Thyroidectomy will be a poor option for patients with multiple previous neck operations on or around the thyroid due to internal scarring, or who are high risk for general anesthesia. Additionally, if they have a history of previous gastric bypass surgery, they are higher risk for major complications from hypocalcemia/hypoparathyroidism after thyroidectomy.

To help the patient navigate these decisions, it is important to allow them the opportunity to discuss each treatment option with respective physician experts – medical management with endocrinology, RAI with endocrinology and potentially nuclear medicine as well, and thyroidectomy with the thyroid surgeon.

In summary, patients with hyperthyroidism require medical control, as well as a clear understanding of the etiology of their hyperthyroidism. Patients with Graves disease, toxic multinodular goiter and toxic adenoma have more than one treatment option, and it is important for patients to be educated and engaged in treatment decisions.

For Further Reference:
American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis| by the American Thyroid Association

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.

The post Thyroid Health Blog: Hyperthyroidism Awareness appeared first on American Thyroid Association.

Anaplastic or undifferentiated thyroid cancer is a rare but extremely deadly form of thyroid cancer. It constitutes only 1-2% of thyroid cancer cases but accounts for over 30% of thyroid cancer related mortality. It has, for the longest time, escaped all attempts to change its dismal prognosis – historically having a median survival of 4-6 months and very few, if any, long-term survivors. Progress in anaplastic thyroid cancer has been slow because it is refractory to standard chemotherapies and because of its rarity, which make clinical trials very challenging. It is therefore exciting to see that this is gradually beginning to change, and the standard treatment recommendation for patients with metastatic disease is no longer just hospice care.

A breakthrough happened when molecular diagnostic testing came about for thyroid tumors. A basket trial in BRAF mutant rare cancers (that also happened to include 16 patients with BRAF V600E mutant anaplastic thyroid cancer) showed that patients who have BRAF mutant anaplastic thyroid cancer and were treated with the RAF/MEK inhibitor combination dabrafenib/trametinib had radiographic responses that were durable in many cases beyond one year. [1] This therapy is now an FDA approved treatment option.

Immunotherapy, which promotes the body’s own immune defense mechanisms to find and destroy cancerous cells, has revolutionized cancer care and is also beginning to make its mark in anaplastic thyroid cancer treatment. The PD-1 inhibitor, spartalizumab, was associated with a 19% response rate. [2] Nivolumab plus ipilimumab (also PF-1 inhibitors) led to profound radiographic responses in 4/10 patients in a phase 2 study, and some of the responses were durable beyond the intended treatment duration of 2 years. [3]

The proto-oncogene RET is primarily known as a driver mutation in medullary thyroid cancer. Another molecular alteration that can lead to RET activation are RET fusions, which can occur in approximately 15% of all papillary thyroid cancer cases and also likely occur at a similar rate in anaplastic thyroid cancer. The novel RET specific tyrosine kinase inhibitors, selpercatinib and pralsetinib, have been tested in a limited number of cases with anaplastic thyroid cancer. It appears that the disease frequently responds to these drugs but resistance seems to emerge rather quickly in most cases. [4]

Other molecular abnormalities such as activating mutations along the PI3K/mTOR axis are also quite frequent, occurring in approximately 30% of cases and in these cases. The mTOR inhibitor everolimus has shown efficacy although confirmation in larger prospective studies is lacking. [5, 6] .

It is very satisfying to see that finally real treatment options have emerged to help patients with this awful disease.

For Further Reference:
American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer  | by the American Thyroid Association
Note: An UPDATE to ATA’s Anaplastic Thyroid Cancer Guidelines is anticipated to be published/available early 2021.

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.

References:

1. Subbiah, V., et al., Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. J Clin Oncol, 2018. 36(1): p. 7-13.
2. Capdevila, J., et al., PD-1 Blockade in Anaplastic Thyroid Carcinoma. J Clin Oncol, 2020: p. JCO1902727.
3. Lorch, J.H., et al., A phase II study of nivolumab (N) plus ipilimumab (I) in radioidine refractory differentiated thyroid cancer (RAIR DTC) with exploratory cohorts in anaplastic (ATC) and medullary thyroid cancer (MTC). Journal of Clinical Oncology, 2020. 38(15_suppl): p. 6513-6513.
4. Subbiah, V., et al., Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors. Journal of Clinical Oncology, 2020. 38(15_suppl): p. 109-109.
5. Wagle, N., et al., Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med, 2014. 371(15): p. 1426-33.
6. Harris, E.J., et al., Everolimus in Anaplastic Thyroid Cancer: A Case Series. Front Oncol, 2019. 9: p. 106.

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Thank you!

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CAMBRIDGE, Mass. – Genzyme, a Sanofi company (EURONEXT: SAN and NYSE: SNY), today announced the Food and Drug Administration (FDA) approved revised prescribing information for the use of Thyrogen® (thyrotropin alfa for injection) to widen the dose range of radioiodine (RAI) when used for thyroid remnant ablation. Read More…

THYROGEN^® Highlights of Prescribing Information (PDF File, 666KB)

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We are excited about this new initiative and involvement with our CLC partners.  Should you have any questions, please don’t hesitate to contact us via email – mailto:clc@thyroid.org.

We look forward to seeing our partners at the 4th Annual Meeting of the ATA CLC in San Juan, Puerto Rico during the 83rd Annual Meeting of the ATA, October 16 – 20, 2013.  

Corporate Leadership Council of the American Thyroid Association 6066 Leesburg Pike, Suite 550, Falls Church, VA 22041 clc@thyroid.org | www.thyroid.org

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