Family Medicine Refresher Course April 5, 2018 Common Issues in Management of Hypothyroidism Family Medicine Refresher Course April 5, 2018 Janet A. Schlechte, M.D.

Disclosure of Financial Relationships Janet A. Schlechte, M.D. has no relationships with any proprietary entity producing health care goods or services consumed by or used on patients.

Issues The symptomatic patient with normal thyroid function studies. Is there a role for T3 or combination T4/T3 therapy? Thyroid disease during pregnancy. Subclinical thyroid disease. Recognizing secondary hypothyroidism.

Evaluating the Thyroid Free T4 T3 Reverse T3 TSH Free T3 TPO Ab TSI

Thyroid Ultrasound Skin Strap Muscles Carotid Left Lobe Rt. lobe Trachea

Thyroid Ultrasound Too sensitive for screening Measures size and number of nodules Not a substitute for the physical exam At least 50% of general population has small nodules by ultrasound An ultrasound cannot distinguish benign and malignant nodules Not assess function

Won’t need a scan often Use when you want to know function of the nodule

HOT COLD Hot nodules will have ↓ TSH or signs of hyperthyroidism Most nodules are cold

A 40 y.o. has developed fatigue, cold intolerance, constipation and weight gain since her last visit. Her exam is normal and the thyroid is not palpable. You suspect hypothyroidism and order thyroid function studies.

FT4 0.7 (0.8-1.8) TSH 25 (0.2-4.2) Most likely diagnosis is autoimmune hypothyroidism Levothyroxine 1.6 µg/kg except in heart disease or elderly Repeat TFT’s in 10-12 weeks

One year later FT4 1.2 (0.8-1.8) TSH 4.9 (0.2-4.2) Two years later FT4 1.3 (0.8-1.8) TSH 45 (0.2-4.2) Three years later TSH is 2, she is constipated and she can’t lose weight

The symptomatic patient with normal TFT’s “Using the wrong tests” “The TSH normal range is wrong” “I need both T4 and T3” “I need natural thyroid hormone” “I need a higher dose” “My thyroid is not converting T4 to T3” Study in Germany excluded patients with FH, nodules, +TPO or goiter

Is the TSH assay wrong? Will maintaining TSH at the upper or lower ends of the normal range improve symptoms? Should you use symptoms or TSH levels to guide therapy with thyroid hormone?

Effect of Targeting High and Low Ends of TSH Normal Range Double blind randomized trial TSH 0.3-4.8 Doses of T4 in random order - Low dose 2.0-4.8 - Middle dose 0.3-1.9 - High dose <0.3 Patients maintained on variable doses for 1 year JCEM 91:2624, 2006

No Significant Treatment Effect Well being Hypothyroid symptoms Quality of life Cognitive function Treatment preference JCEM 91:2624 2006

TSH Levels and Changes in Body Composition Percent change in BMI, percent change in body fat, and absolute change in LDL cholesterol in patients maintained for one year with TSH values of approximately 3 mlU/L (black bars) and approximately 1 mlU/L (gray bars). TSH differences are significant; differences in other parameters are non-significant. Thyroid 21: 355, 2011

Take Home Points Small changes in levothyroxine do not produce measurable changes in hypothyroid symptoms or well being TSH target for hypothyroidism should not differ from the general reference range Changing upper limit of normal TSH to 2.5 would increase the number of patients with subclinical hypothyroidism and there is no consensus that subclinical disease (TSH 5-10) requires treatment

A 40 y.o. has been taking thyroid hormone for 6 months but didn’t bring the pills to her clinic visit. Because she is fatigued her dose has been steadily increased over the last 3 months. Now her complaints are tachycardia and heat intolerance. Labs today: free T4 0.6 (0.8-1.8) and TSH 0.01 (0.2-4.2). What is wrong with this picture?

What is the best thyroid hormone replacement? Levothyroxine (T4) Triiodothyronine (T3) Combination T4/T3 “Natural” thyroid hormone

T4 and T3 Concentrations After Thyroid Hormone . T4 T3 T4 T3 Normal Range Hours After T3 Hours After T4

Avoid T3 in Treatment of Hypothyroidism Short half-life Risky in elderly and in those with CV disease If you must use it monitor TSH to assess adequacy of dose Many labs don’t do routine T3 or free T3 assays JAMA 299, 2008

A 79 y. o. has taken 1½ grains of Armour thyroid for 20 years A 79 y.o. has taken 1½ grains of Armour thyroid for 20 years. Now she is fatigued, has lost weight and has constipation. Her BMI is 26 and her thyroid is not palpable. Her B/P is 120/80 and pulse is 88. FT4 0.6 (0.8-1.8), TSH 1.2 (0.2-4.2), T3 2.1 (0.8-2). What should you recommend? Increase dose by ½ grain Decrease dose by ½ grain Change to levothyroxine Continue current therapy

“Natural” Thyroid Hormone Armour thyroid extract 1 grain contains 38 µg T4 and 9 µg T3 roughly equivalent to 74 µg of levothyroxine Batch to batch variability Not always readily available Unless you only measure TSH, results can be confusing

Thyroid makes both T4 and T3 Is combination therapy more effective? TRH Hypothalamus Thyroid makes both T4 and T3 Is combination therapy more effective? + Anterior Pituitary TSH Thyroid gland + T4, T3 T3 Target cells throughout body

Randomized Trials Comparing Combination T4 /T3 vs T4 Alone 8/9 randomized trials showed no difference in - quality of life - cognitive function - psychometric performance - treatment preference Combinations do not replicate physiologic T4/T3 production JCEM 91:2592, 2006

Combination Therapy JCEM 91: 2592, 2006

American Thyroid Association Take Home Points American Thyroid Association Patients with hypothyroidism should be treated with levothyroxine as monotherapy Levothyroxine is treatment of choice due to long term experience, favorable side effect profile, ease of administration, long half-life and low cost Thyroid 24:1670, 2014

How can we help the symptomatic patient who has normal TFT’s? Be sympathetic but don’t try to fix all problems with thyroid hormone Don’t over replace or change therapy based on symptoms alone Eventual understanding of molecular regulation of thyroid hormone may lead to better understanding of how to treat

A 40 y. o. with longstanding hypothyroidism has a FT4 1. 5 (0. 9-1 A 40 y.o. with longstanding hypothyroidism has a FT4 1.5 (0.9-1.5) and TSH < 0.01 (0.2-4.2) at a routine visit. She takes 0.15 mg of levothyroxine daily. Her pulse is 96, BP 110/80 and she has hyperactive reflexes. You recommend lowering the dose but she is worried about gaining weight. She asks “is there any harm in letting TFT’s run a little high?”

Risk of Fracture in Women with Low TSH Hip Vertebral NonSpine Ann Intern Med 2001 30

Incidence of Atrial Fibrillation in Subclinical Hyperthyroidism 30 20 Percent with Atrial Fibrillation 10 TSH ≤ 0.1 mU/L TSH 0.1-0.4 mU/L TSH ≥ 0.5 mU/L NEJM 331:1249, 1994

A 42 y.o. man had these tests at a visit to Neurology for evaluation of headaches. The headaches have improved, he feels great, his exam is normal and the thyroid is not enlarged. FT4 1.2 (0.8-1.8) TSH 5.2 (0.2-4.2) What is the next step?

Subclinical Hypothyroidism Normal FT4 Mildly  TSH Asymptomatic Prevalence higher in women ~30% may develop hypothyroidism

Levothyroxine vs placebo Thyroid Hormone Therapy for Older Adults With Subclinical Hypothyroidism 737 adults TSH 4.6-10 Levothyroxine vs placebo Changes in hypothyroid symptoms and tiredness score at 1 year No apparent benefit in older patients NEJM 376:2534, 2017

Elevated antithyroid antibodies Whether to Treat Subclinical Hypothyroidism is Controversial One Approach Enlarged gland Hyperlipidemia TSH >10 mU/L Elevated antithyroid antibodies

A 40 y.o. complains of fatigue, amenorrhea, cold intolerance, dry skin and weight gain. Six months ago in your office her TSH was normal.

Today she has the same complaints along with constipation Today she has the same complaints along with constipation. On exam she has delayed DTR’s. Her TSH is 1 (0.2-4.2) and you reassure her that her thyroid is ok. One month later she is back feeling worse and she also complains of severe headaches. What is wrong with this picture?

Secondary Hypothyroidism FT4 and TSH Patient may have hypopituitarism Measuring TSH alone may miss or delay diagnosis

A 35 y.o. has had amenorrhea since the birth of her second child 1½ years ago. She has noted a 10 pound weight gain, constipation and cold intolerance. On exam she has dry skin and periorbital puffiness and her thyroid is smooth and not enlarged. Her TSH is 0.9 (0.2-4.2) and a repeat TSH is 1.1

How can she have such prominent symptoms of hypothyroidism and a normal TSH? What test will confirm your suspicion of hypothyroidism?

Secondary Hypothyroidism Symptoms and replacement therapy are the same as in primary hypothyroidism Monitor replacement with free T4 Evaluate the pituitary adrenal axis as patient may also have adrenal insufficiency

Screening for Hypothyroidism in Pregnancy Universal screening is controversial Use targeted approach - history of autoimmune disease - family history of thyroid disease - history of elevated TPO antibodies - recurrent miscarriage - history of head or neck irradiation - BMI >40 kg/m2

Hypothyroidism in Pregnancy Requirements for thyroid hormone may increase by 50% When hypothyroidism diagnosed, adjust dose and repeat levels every 30-40 days Requirements will decrease after delivery Thyroid 21:1081, 2011

Trimester Specific TSH 0.1-2.5 1st trimester 0.2-3.0 2nd trimester 0.3-3.0 3rd trimester

Low Maternal Free T4 Isolated maternal hypothyroxinemia and normal TSH Effect on perinatal and neonatal outcome is unclear Isolated low free T4 during second trimester not associated with cognitive dysfunction (JCEM 2012) Guidelines do not support treatment (Thyroid 21:1081, 2011)

References ATA Guidelines - Thyroid Nodule. Thyroid 26:1200, 2016. ATA Guidelines - Hypothyroidism. Thyroid 24:1670, 2011. ATA Guidelines – Pregnancy. Thyroid 21:593, 2011.