#208 Hypothyroidism Master Class with Susan Mandel MD, MPH

April 20, 2020 | By Elena Gibson

How to dominate the diagnosis and management of hypothyroidism

Fall in love with the thyroid all over again, as we deconstruct hypothyroidism with thyroid expert, Susan Mandel MD, MPH (PENN). We review common causes, symptoms, diagnosis and treatment and how these may differ for those who are Pregnant, over age 65, or have existing Heart disease. Plus, Dr Mandel schools us on her approach to treatment with levothyroxine (T4), and even explains when she trials liothyronine (T3) replacement! Warm up those thumbs for the thyroid exam…it’s on!

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Credits

• Written and Produced by: Elena Gibson MD 
• Cover art and Infographic by: Dr Kate Grant MBChb MRCGP
• Hosts: Stuart Brigham MD; Matthew Watto MD, FACP; Paul Williams MD, FACP   
• Editor: Emi Okamoto (written materials); Clair Morgan of nodderly.com
• Guest: Susan Mandel MD, MPH

Sponsor

We are excited to announce that the Curbsiders are now partnering with VCU Health Continuing Education to offer continuing education credits for physicians and other healthcare professionals. Check out https://curbsiders.vcuhealth.org/ for more information.

Time Stamps

• 00:00 Intro, disclaimer, guest bio
• 02:43 Guest one-liner; Pick of the week: Waiting for Godot (Play); Favorite Failure; Career Advice
• 09:40 Case from Kashlak Part one; Hypothyroidism signs and symptoms
• 13:20 When to Test for Hypothyroidism
• 17:43 Biotin interaction
• 19:49 Which thyroid tests should we order?
• 26:15 Subclinical hypothyroidism
• 29:00 Etiology/Types of hypothyroidism
• 33:30 Case from Kashlak Part two; Initial Medication dosing; Physical Exam
• 37:10 Levothyroxine replacement time of administration
• 42:10 TSH goal
• 46:00 Levothyroxine manufacturers
• 48:33 Dosing in older adults
• 50:27 T3 treatment
• 56:52 Pregnancy
• 59:42 Dose adjustments
• 61:43 Estrogen and thyroid binding protein
• 63:33 Who needs a referral?
• 65:40 Plugs, Outro

Hypothyroidism Pearls

1. Autoimmune destruction of the thyroid is the most common cause of hypothyroidism in populations where iodine deficiency is rare (including the US). 
2. Less common causes of hypothyroidism include radiation induced and central hypothyroidism (think anyone with a brain injury). 
3. Overt hypothyroidism is defined by an elevated TSH and low T4 level. 
4. Subclinical hypothyroidism (elevated TSH on two checks, normal T4 level) should be treated when the TSH >10 in all patients,  >7 in patients <65 years old, and >upper limit of normal in pregnant patients.
5. TSH levels are not distributed normally, and ~95% of euthyroid individuals have a TSH <2.5. 
6. Levothyroxine replaces T4 produced by the thyroid and is the treatment of choice for hypothyroidism. 
7. There is no population-level evidence to support the use of levothyroxine and liothyronine (T3) combination treatment in hypothyroidism.
8. Pregnancy increases the amount of levothyroxine required for hypothyroidism, and dosage adjustments are important during the first trimester before the first common antenatal care visit .

Hypothyroidism Show Notes 

Causes of Hypothyroidism

The most common cause of hypothyroidism in iodine-sufficient populations is Hashimoto’s, or autoimmune destruction of the thyroid (Chaker 2017). Worldwide, the most common cause is iodine deficiency (Garber 2012). Autoimmune destruction of the thyroid is more common in women, patients with other autoimmune disorders (Type I DM, lupus, rheumatoid arthritis, celiac disease, Addison’s disease), and caucasians (Chaker 2017, Aoki 2007). Less common causes of hypothyroidism to consider include radiation induced hypothyroidism (after head and neck cancer or lymphoma), central hypothyroidism (primary pituitary disorders, traumatic brain injury [TBI]), and surgical hypothyroidism (surgical treatment for hyperthyroidism or thyroid cancer) (Garber 2012). Remember to consider central hypothyroidism in patients with prior TBI or athletes with repetitive head trauma (Sav 2019). 

Diagnosing Hypothyroidism 

There are many symptoms that can be associated with disorders of thyroid function. Multiple organs respond to thyroid hormone by altering gene expression in addition to non-genomic effects. Furthermore, similar thyroid hormone levels in different people can lead to very different symptoms. Although recommendations vary between guidelines, screening for hypothyroidism in an asymptomatic individual is not recommended and has not been proven to be cost effective (Cooper 2012, LeFevre 2015). However, patients with signs and symptoms of hypothyroidism should be tested, and a variety of signs and symptoms exist (Chaker 2017)

Signs and Symptoms 

Common, but nonspecific, symptoms of hypothyroidism include fatigue, menstrual irregularities, dry skin, and mood changes. Weight gain, myxedema and diffuse goiters are rare and usually only identified in severe hypothyroidism(Chaker 2017). Dr. Mandel reminds listeners to screen for hypothyroidism in young patients with new depression, infertility,  or menstrual cycle changes. In older patients, signs/symptoms that should trigger screening for thyroid disease include hyperlipidemia, cognitive decline, tachyarrhythmias (hyperthyroidism), and osteoporosis (hyperthyroidism). Ask all patients about personal and family history of autoimmune disorders or thyroid disease as hypothyroidism is more common when either are present (Chaker 2017). Additional risk factors for hypothyroidism to ask about include prior radioiodine treatment for hyperthyroidism, radiation therapy for head/neck cancer or lymphoma, and surgical treatment for thyroid cancer or hyperthyroidism (Garber 2012). 

Physical Exam

Dr. Mandel recommends palpating the thyroid from the front of the patient’s neck using your thumbs to roll down the midline of the trachea starting around the thyroid cartilage and moving inferior. She recommends rolling your thumbs until you find the isthmus,  a “speed bump or stretched gummy worm” that inserts into the lower ⅓ of the thyroid near the cricoid cartilage (Simmel 2009). After locating the isthmus, use your thumbs to palpate medially on either side to feel the lobes of the thyroid against the tracheal cartilage for support. Palpate for any evidence of an enlarged goiter or nodules that warrant additional evaluation. 

Kashlak Pearl: Dr. Mandel recommends using your thumbs to palpate the thyroid gland! Who knew?

Thyroid Stimulating Hormone (TSH) 

Signs and symptoms of hypothyroidism alone are neither sensitive nor specific, so thyroid hormone testing is necessary to establish a diagnosis. TSH testing alone is sufficient unless there is reason to suspect central hypothyroidism from pituitary or hypothalamic dysfunction (pituitary tumor, radiation history, traumatic brain injury). If there is no concern for central hypothyroidism and the TSH is normal then hypothyroidism is ruled out. If the TSH is abnormal, the free T4 is used to define overt vs. subclinical hypothyroidism and to help guide initial treatment (Garber 2012). If there is concern for central hypothyroidism from pituitary or hypothalamic dysfunction (pituitary tumor, radiation history, traumatic brain injury), then initial testing should include both TSH and free T4 (Garber 2012). 

Overt Hypothyroidism 

TSH is higher than the normal reference range and the free T4 is low. Use the TSH to guide treatment and aim for a TSH in the normal, age-specific reference range. 

Subclinical hypothyroidism (See more below) 

Elevated TSH with a normal free T4. TSH should be repeated, at least a month apart (or sooner if pregnant). Treatment depends on age and TSH level.

Central hypothyroidism 

Both the TSH and free T4 are lower than the normal reference range. Free T4 levels should be used for treatment management (Garber 2012). 

Biotin and TSH 

Per Dr Mandel, the recommended dose of biotin is about 70mcg and many people take daily hair/nail supplements that contain approximately 5K-10K mcg of biotin. Biotin can affect both TSH and T4/T3 measurements. TSH is measured using an immunometric assay,  a sandwich antibody test with a TSH molecule between two biotinylated antibodies. When biotin levels are high, the biotin binds the antibodies and prevents the antibodies from binding to the TSH. Therefore, the TSH is not captured when taking high levels of biotin, so the TSH level can be falsely low. Additionally, biotin can also cause falsely elevated levels of  free T4, total T4 and total T3 as these are measured using biotinylated antibodies with competitive assays. Overall, this can lead to a falsely low TSH and falsely elevated levels of T4 and T3, congruent with a biochemical diagnosis of thyrotoxicosis (Li 2017). There have even been case reports of patients being inappropriately treated with methimazole. 

Kashlak Pearl: Dr. Mandel tells patients to avoid biotin supplements for 2-3 days prior to thyroid testing to avoid falsely low TSH.

TPO Antibodies 

Dr. Mandel rarely orders TPO antibodies because the result infrequently changes management. For example, if the TSH is 20, the treatment is levothyroxine with or without positive TPO antibodies. Instead of ordering antibodies on every patient, Dr. Mandel recommends checking TPO antibodies to differentiate if a patient with subclinical hypothyroidism is likely to progress to overt hypothyroidism or subclinical hypothyroidism warranting treatment as positive antibodies are associated with progression (Cooper 2012).

Subclinical Hypothyroidism: when to treat? 

Subclinical hypothyroidism is defined as an elevated TSH with a normal free T4 (Cooper 2012). Depending on the studied population, treatment of subclinical hypothyroidism has been associated with prevention of adverse cardiovascular outcomes, improved hyperlipidemia and improvement in menstrual irregularities (Rodondi 2010, Cooper 2012). 

TSH > 10, normal free T4

In all ages, this is significant subclinical hypothyroidism and one should consider treatment (Jonklaas 2014).

Age < 65 with subclinical hypothyroidism

Treating subclinical hypothyroidism in younger patients (<65 years old) with a TSH >7 is sometimes done because it has been associated with reduced adverse cardiovascular outcomes (Biondi 2019). For patients under the age of 65, some guidelines recommend treating if TSH is >7, and treatment should be considered if TSH >5  and symptoms are present (Cooper 2012). Any subclinical hypothyroidism in pregnancy should be treated (Cooper 2012, Biondi 2019).

Age >70  with subclinical hypothyroidism

It is important to consider how the normal TSH range shifts upwards with age, and a TSH of 6-7 in an elderly patient could be normal. Furthermore, treatment of subclinical hypothyroidism is not recommended in elderly patients unless the TSH is >10 because observational data has identified associations between higher TSH levels and improved mortality and well-being in elderly patients (Jonklaas 2014). 

Hypothyroidism Treatment

Levothyroxine provides T4 replacement and is the treatment of choice for hypothyroidism. The thyroid makes two thyroid hormones T4 and T3,  named for the number of iodine molecules they contain (T4 has 4 and T3 has 3). T3 is the active hormone that enters the nucleus of cells and activates hormone receptor genes (Jonklaas 2014). Provided the body has sufficient iodine, the thyroid alone makes 100% of T4 and ~20% of T3. Although levothyroxine does not replace the 20% of T3 from the thyroid, the remaining ~80% of T3 is made in the liver or elsewhere in the body where enzymes remove an iodine from T4 to make active T3 (Jonklaas 2014). 

Levothyroxine  

Initial Dosing:  

In a young healthy patient (overt or subclinical hypothyroidism), start levothyroxine at a full treatment dose of 1.6ug/kg (Jonklaas 2014). In patients with an elevated BMI, consider a dose reduction as recent data suggests a need to dose more towards ideal body weight (Papoian 2019). In elderly the metabolism of thyroid hormone slows down, so lower doses are frequently required (Jonklaas 2014). For patients over 65 to 70 years old, Dr. Mandel recommends treatment should “start low and go slow” unless the patient requires full supplementation following a thyroidectomy. Start low at 25-50mcg (25mcg if cardiovascular disease) then increase by small increments of 12.5 to 25mcg with a target TSH in the high/normal range of 4-6. Cautious escalation of therapy should also be considered in patients with a history of cardiac disease to avoid precipitating angina. 

Absorption: 

Seventy five percent of oral thyroid hormone is absorbed under normal conditions, and various factors can interfere with thyroid absorption. Iron supplements, soy protein, multivitamins, prenatal vitamins will decrease thyroid hormone absorption.  Given the 7 day half life of levothyroxine, the medication can be taken at any time of day, including at night before sleeping. Data supports that the medication will be absorbed well as long as it is taken 3 hours before or after a meal, and Dr. Mandel reinforces how consistency is the most important factor (Jonklaas 2014). Although meals can interfere with absorption, if the same type of meal is eaten around the time of the levothyroxine, the dosing shouldn’t require as much adjustment. Problems are more likely to occur with changes in dietary patterns such as new intermittent fasting. In lower resource settings levothyroxine can even be dosed once per week (Jonklaas 2014). However, this can lead to additional issues with taking high doses infrequently, and it is not as physiologic. 

Kashlak Pearl: Levothyroxine will be absorbed well as long as it is taken 3 hours before or after a meal. That said, patients’ quality of life is paramount and Dr. Mandel reinforces how consistency is the most important factor (e.g. take it 30 minutes before breakfast everyday).

Timing: 

When initiating levothyroxine treatment, Dr. Mandel reviews how the medication will not work like acetaminophen or ibuprofen. Patients should not expect to feel better in hours, days or even two weeks because the half life is 7 days long. A repeat TSH is checked at 6 weeks because when the thyroid hormone reaches equilibrium (Jonklaas 2014). 

Kashlak Pearl: Dr. Mandel has noticed that the resolution of symptoms from hypothyroidism usually lags behind TSH normalization by 2 to 3 months. 

Manufacturer differences: 

The  FDA determines equivalency by looking at the area under the curve and time to maximal concentration of two thyroid hormone replacement medications, and they are deemed equivalent. However, problems arise in practice as clinical adequacy is determined  by measuring TSH levels, not medication levels. Therefore, if a patient switches from one brand to another, it is recommended to recheck a TSH level to ensure appropriate treatment (Jonklaas 2014). As generics are determined by pharmacy contracts, Dr. Mandel asks patients to call for a TSH check if they notice a difference in the shape/color of  their levothyroxine pill. For most patients with hypothyroidism, this probably isn’t a huge deal because it might be the difference between a TSH of 0.8 and 3,  but worrisome problems may arise in patients requiring more narrow control of TSH, such as patients with thyroid cancer (Jonklaas 2014).

Kashlak Pearl: Dr. Mandel asks patients to call for a TSH check if they notice a difference in the shape/color of  their levothyroxine pill.

Treating to TSH 

The distribution TSH levels in euthryoid individuals used to establish a normal reference range (usually 0.4-4.0mIU/L) is not a bell shaped curve, and 95% of patients have TSH levels <2.5 mIU/L (Razvi 2019). Therefore, clinicians have historically aimed for a TSH in the lower range of normal, but no clear benefit has been associated with adjusting treatment to lower TSH goals in current literature (Jonklaas 2014). One cross-over study by Walsch et al. found no difference in patient reported symptoms between different treatment doses resulting in three different mean TSH levels within the reference range (Walsch 2006). Similarly a randomized trial by Samuels et al. of treatment to lower half, upper half and above normal reference range TSH goals did not identify a relationship with TSH level and quality of life,mood or cognition (Samuels 2018). Although the evidence does not support lower TSH goals, Dr. Mandel aims for a goal TSH of 0.5-3.0 in most patients, due to anecdotal evidence of improved symptoms and TSH levels seen in euthyroid patients. Excessive levothyroxine can lead to iatrogenic hyperthyroidism (TSH below normal reference range), and should be avoided due to increased risk of fracture and atrial fibrillation (Jonklaas 2014). Some guidelines recommend treating to a higher TSH goal of 4-6 in patients >70 years old (Jonklaas 2014). 

The TSH should be checked every 6 weeks while titrating a dose and yearly to ensure appropriate dosing after a treatment dose is established (Jonklaas 2014). 

T3 Testing and Treatment 

With new T3 products available many patients ask about the utility of T3 testing and replacement. 

T3 Testing

When asked about T3 testing, Dr. Mandel discusses the importance of considering how T3 production changes with demand.  Throughout the day, T4 is converted to T3 on an as needed basis. Dr. Mandel explains how T3 levels in the morning after fasting or after running are very low, and levels spike after eating when additional conversion is needed for metabolism. Therefore, a single snapshot of T3 does not provide a true representation of the demand based conversion and homeostasis the body maintains. 

Treatment with T3

Most patients do well on levothyroxine alone, and population-level research has not identified any benefit to treating hypothyroidism with levothyroxine (T4) and liothyronine (T3) compared to levothyroxine alone (Jonklaas 2014). However, in Dr. Mandel’s opinion there are some patients that improve when the 20% of T3 made by the thyroid is replaced. Dr. Mandel considers trialing T3 treatment in patients with a TSH in the normal range or lower part of normal with ongoing cognitive symptoms (decreased attention, mental fog), after ruling out sleep disorders. Treating with T3 is challenging because there is no long acting T3 like levothyroxine. Liothyronine (T3) peaks and troughs in 3 hours, so it requires at least twice per day (morning and 2-3pm) dosing and Dr. Mandel recommends avoiding doses of >5mcg at one time. Importantly, levothyroxine (T4) and liothyronine (T3) should be dosed to achieve the physiologic T4:T3 ratio of 14 to 1(Jonklaas 2014). Dr. Mandel advises against using the extract because it has a fixed ratio of 4:1. Additionally, she avoids T3 use in older patients, those with any history of coronary artery disease, and pregnant patients given the potential effects on the heart and inability to cross the placenta. 

Pregnancy and Hypothyroidism  

When a woman is diagnosed with hypothyroidism, Dr. Mandel recommends immediate counseling on the importance of thyroid hormone adjustment before and during pregnancy.  Additional levothyroxine is needed during pregnancy, and dose adjustments could be necessary as early as 6 weeks (Mandel 1990). Fetal development relies on maternal T4 during the first trimester, so patients should let a provider know as soon as possible instead of waiting until the first trimester appointment (usually around 11-12 weeks) (Patel 2011). Required levothyroxine dose increases vary from approximately 25-40% based on how much functioning thyroid the mother has left, with higher dose adjustments required for surgical hypothyroidism compared to autoimmune (Jonklaas 2014). Until a pregnant patient is able to have thyroid function testing completed, Dr. Mandel will often recommend  taking 2 extra pills per week to avoid low thyroxine levels. Furthermore, remind patients to take their prenatal vitamin and levothyroxine at different times to avoid decreased levothyroxine absorption. Postpartum, dosing should return to the same dose before pregnancy and there are no changes required while breastfeeding (Garber 2012).

Kashlak Pearl: Fetal development relies on maternal T4 during the first trimester. Therefore, until a pregnant patient is able to have thyroid function testing completed, Dr. Mandel recommends taking 2 extra pills per week to avoid low thyroxine levels.

Estrogen and TSH 

Required levothyroxine dosing increases during pregnancy due to estrogen’s effect on thyroid binding protein, and similar dosage adjustments are seen with estrogen containing birth control pills and hormone replacement therapy.  Progesterone only birth control pills and progestin IUDs do not change dose requirements (Jonklaas 2014, Garber 2012). 

Links

1. Waiting for Godot, play by University of Chicago Arts
2. American Thyroid Association website – for guidelines and patient information

Goal

Listeners will develop an approach to the diagnosis and management of patients with hypothyroidism.

Learning objectives

After listening to this episode listeners will…  

1. Recognize the different etiologies of hypothyroidism.
2. Identify signs and symptoms of hypothyroidism.
3. Develop an approach to diagnosing and treating hypothyroidism.
4. Define subclinical hypothyroidism and when to treat it. 
5. Recognize how pregnancy influences hypothyroidism management.
6. Be able to counsel patients on treatment for hypothyroidism.

Disclosures

Dr. Mandel reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Mandel S, Gibson EG, Grant K, Williams PN, Brigham SK, Okamoto E, Watto MF. “Hypothyroidism”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list April 20, 2020.

References

1. Chaker L et al. Hypothyroidism. Lancet. 2017. [https://www.ncbi.nlm.nih.gov/pubmed/28336049]
2. Garber, JR et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012.[https://www.ncbi.nlm.nih.gov/pubmed/23246686]
3. Aoki, Y. et al. Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002). Thyroid. 2007. [https://www.ncbi.nlm.nih.gov/pubmed/18177256]
4. Sav A et al. Pituitary pathology in traumatic brain injury: a review. Pituitary. 2019. [https://www.ncbi.nlm.nih.gov/pubmed/30927184]
5. Cooper DS & Biondi B . Subclinical thyroid disease. Lancet. 2012. [https://www.ncbi.nlm.nih.gov/pubmed/?term=22273398]
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7. Simel DL & Rennie D. eds. The Rational Clinical Examination: Evidence-Based Clinical Diagnosis New York, NY: McGraw-Hill; 2009. [http://jamaevidence.mhmedical.com/content.aspx?bookid=845&sectionid=61357508] 
8. Jonklaas J et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014. [https://www.ncbi.nlm.nih.gov/pubmed/25266247]
9. Li, D et al. Association of Biotin Ingestion With Performance of Hormone and Nonhormone Assays in Healthy Adults.JAMA. 2017. [https://www.ncbi.nlm.nih.gov/pubmed/?term=28973622]
10. Rodondi, N et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. Jama. 2010. [https://www.ncbi.nlm.nih.gov/pubmed/20858880]
11. Biondi, B et al. Subclinical Hypothyroidism: A Review. Jama. 2019. [https://www.ncbi.nlm.nih.gov/pubmed/31287527]
12. Papoian, V et al. Evaluation of Thyroid Hormone Replacement Dosing in Overweight and Obese Patients After a Thyroidectomy. Thyroid. 2019. [https://www.ncbi.nlm.nih.gov/pubmed/31573413]
13. Razvi et al. Challenges in Interpreting Thyroid Stimulating Hormone Results in the Diagnosis of Thyroid Dysfunction. J Thyroid Res. 2019. [https://www.ncbi.nlm.nih.gov/pubmed/31662841]
14. Walsh, JP et al. Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life: results of a double-blind, randomized clinical trial. J Clin Endocrinol Metab.2006. [https://www.ncbi.nlm.nih.gov/pubmed/16670161]
15. Samuels, MH et al. Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects. J Clin Endocrinol Metab. 2018. [https://www.ncbi.nlm.nih.gov/pubmed?term=29509918]
16. Mandel, SJ et al. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med. 1990. [https://www.ncbi.nlm.nih.gov/pubmed/2359428]
17. Patel, J et al. Thyroid hormones and fetal neurological development. J Endocrinol. 2009. [https://www.ncbi.nlm.nih.gov/pubmed/21212091]
18. Surks MI & Hollowell JG.  Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007. [https://www.ncbi.nlm.nih.gov/pubmed?term=17911171]

19. Clyde, et al. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. Jama. 2003. 
20. Bauer, D. C., Ettinger, B., Nevitt, M. C., & Stone, K. L. (2001). Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med, 134(7), 561-568. 
21. Patel, J., Landers, K., Li, H., Mortimer, R. H., & Richard, K. (2011). Thyroid hormones and fetal neurological development. J Endocrinol, 209(1), 1-8. [https://www.ncbi.nlm.nih.gov/pubmed/21212091]
22. De Groot, L., Abalovich, M., Alexander, E. K., Amino, N., Barbour, L., Cobin, R. H., . . . Sullivan, S. (2012). Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 97(8), 2543-2565.[https://www.ncbi.nlm.nih.gov/pubmed/22869843]