Hypothyroidism: Treating to

Optimal Levels2019 TAFP C. Frank Webber

Sharon Hausman-Cohen, MD

Austin, TX

Speaker Disclosure

Dr. Hausman-Cohen has disclosed that she has no actual or potential conflict of interest in relation to this topic.

Topics Covered – Learning Objectives Develop a screening protocol. Identify patients with thyroid risk factors.

Know which lab tests to order diagnose hypothyroidism and subclinical hypothyroidism.

Prescribe appropriate pharmacotherapy for patients with hypothyroidism and monitor patients accordingly.

Identify a diversity of tissue compartments in which hypothyroidism is consequential.

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A Closer Look at Thyroid Hormones

First a Brief Review

Thyroid Hormone Structures

Most Thyroid Hormone is Bound

Almost all circulating T4 and T3 hormones are bound to serum proteins (thyroid hormone-binding proteins)

Only 0.03% of T4 and 0.3% of T3 are not bound to proteins Free T4 (FT4) and Free T3 (FT3)

What About Reverse T3?

Reverse T3 has an iodine on 1st

ring missing instead of 2nd = inactive.

Reverse T3 levels increase under stress; i.e. with malnutrition and illness

Patients with elevated reverse T3often do not respond well to T4treatment

Endocrinol Diabetes Met Case Rep. 2014; 2014;13055, E-pub 2014 Feb 1

Screening for Hypothyroidism:

Who to screen and how? and

Who not to screen?

Who To Screen: Symptoms: Fatigue, cold intolerance, weight gain,

hair loss, menorrhagia

ALL patients considering pregnancy!!! Patients with medical conditions Depression Heart Failure Hyperlipidemia Growth Delay Osteoporosis And more

When to Order Thyroid Labs

TSH is best screening lab to order for hypothyroidism, as well as hyperthyroidism Most sensitive, specific and reliable test of thyroid

status Inexpensive

Free T4 and sometimes Free T3 are useful for confirmation or assess conversion to T3

Total T3/ T4 not very useful

Afraid to Stop Ordering T3 and T4?

In British Columbia, labs have had standing orders to replace any T3 and T4 ordered with Free T3 and Free T4 for over 8 YEARS!

Used previously as free T3/T4 were costly FT3 / FT4 are each about a $5-7 assay now

Overt Hypothyroidism(Primary Hypothyroidism):

Plasma TSH is : ↑

Plasma Free T4: ↓

Plasma free T3 and total T3 measurements are not helpful for initial screening in most cases, since normal concentrations are often observed.

If patient not responding to treatment, checking for low T3 can be helpful though (i.e. may do with monitoring of treatment) or proactively if cognitive issues.

Subclinical Primary Hypothyroidism

Plasma TSH: High

Thyroid hormone levels (FT4): Normal

Before diagnosing primary subclinical hypothyroidism, other causes of an abnormal TSH must be excluded.

Recovering from Illness (sick Euthyroid)

Pregnancy

Drug treatment

TSH Can Rise After Non Thyroid Illness

During a non thyroid illness, Free T3 and Free T4 levels often drop but TSH can be low or normal

TSH levels then normalize or become high as they recover from their illness

Caution if you obtain a TSH during non thyroid illness

This is Euthyroid Sick Syndrome and generally TSH not treated unless <.1 or >20, recheck when well

Causes of Euthyroid Sick Syndrome

Acute Febrile Illness After Surgery During Fasting After Myocardial Infarction During Malnutrition Renal or Cardiac Failure Hepatic Disease Uncontrolled Diabetes Malignancy

Amiodarone and Hypothyroidism Amiodarone is an iodine rich compound that has a

structure similar to T4

200 mg of Amiodarone gives 100x RDA for iodine

22% of patients will develop Amiodarone-induced hypothyroidism (AIH)

Seniors and women most at risk

3% of patients will develop Amiodarone induced thyrotoxicosis

Gopalan, M. et al. Thyroid Dysfunction Induced by Amiodarone; www.emedicine.medscape.com/article/129033

How Can Amiodarone Cause Both Hypo and Hyperthyroidism?

Amiodarone inhibits T4 T3, so T4 and rT3 increase, but T3 which is more biologically active decreases 20-25%

Amiodarone can also effect the ability for T4 and T3 to enter peripheral tissue

It can also effect the pituitary gland (less deiodination / conversion of the free hormones) so more TSH

SO… DO YOU TREAT THE HIGH TSH?

DO NOT EMPIRICALLY TREAT TSH IN PATIENTS ON AMIODARONE

Check not only TSH but also free T4 and free T3

Watch labs carefully early on as TSH can initially go up but then correct after 2-3 months as T4 increases (enough to compensate for low T3)

Follow clinical signs and symptoms

Even After Stopping Amiodarone,Thyroid Dysfunction May Remain

Amiodarone can have a direct cytotoxic effect on thyroid follicular cells (causing destructive thyroiditis)Amiodarone induced thyroid dysfunction is usually mild but CAN be severe or even fatal so just be aware… In addition, the hypothyroidism 3% of patients develop thyrotoxicosis (males more than females)

Patients on Lithium Also Require Monitoring for Hypothyroidism

3 months after starting lithium, it is recommended to check TSH, anti-TPO (thyroid peroxidase ab) and Antithyroglobulin Antibody

If antibodies positive, higher likelihood of needing thyroid hormone

Follow with TSH q 6-12 months

Treat to lower TSH (closer to .4) to decrease goiter

Lithium and the Thyroid

Lithium acts like iodine and can inhibit thyroid hormone release

Lithium is known best for causing a goiter 20% risk of goiter in iodine sufficient areas

87% risk of goiter in iodine deficient areas

Iodine deficiency is getting more common in USA

Sarlis, N. et al. Lithium Induced Goiter; http://emedicine.medscape.com/article/120243

Lithium Increases Risk of Both Goiter and Hypothyroidism

Goiters induced by lithium often are Euthyroid multinodular goiter

Goiter can cause compressive symptoms

Goiter can start within weeks of starting lithium or within years

Only 5-20% of time will patient develop hypothyroidism• Women more commonly than men

Which of the following are TRUE…

1. Do not treat a high TSH in a patient on Amiodarone without checking FT4

2. Amiodarone can cause a high or low TSH

3. Lithium can cause a goiter

4. 1 and 2

5. All of the above

Prescribe Appropriate Pharmacotherapy for Patients

with Hypothyroidism and Monitor Patients Accordingly

Treatment Options

Levothyroxine*

Combined levothyroxine products with liothyronine of porcine origin*

Separate levothyroxine and liothyronine

*Few different brands will review

Differences Between T3 Preparations

Liothyronine alone comes in 5 or 25 (rarely used) ucg tablets. This is used generally in addition to T4 in ratios of approximately 1:8-17 (5 ucg bid with about 75-125 ucg levothyroxine)

Physiological Ratio of T3:T4 in humans in approximately 1:13

Available porcine sourced products are generally 1:4 (so higher in T3)

Is There a Benefit to Using Combination Thyroid Therapy?

Most Trials of T4 and LT3 combined vs. T4 alone have been small and no clear benefit in overallpopulations using combination vs. T4 alone No difference in psychosocial measures, heart rate,

weight, lipids

Small but significant difference (favoring combination therapy) with regards to less anxiety and less insomnia

Valizadeh, M. et al. Endocr Res. 2009;34(3):80-9. Escobar-Morreale et al. J Clin Endocrinol Metab. 2005 Aug;90(8):4946-54. Epub 2005 May 31

Combination vs. Mono Therapy In a study of 33 patients given blinded courses of

treatment of either T4 alone or T4/T3 combination (12.5 ucg of T3 was used to replace 50 ucg of T4) majority of patients preferred T3/4 combo

20/33 Preferred T3/T4 11/33 No preference 2/33 Preferred T4 alone

Patients on combo reported: More energy, improved concentration, and felt better overall

Subset of Patients May Relate to Gene Variant (Polymorphism)

A polymorphism (Thr92Ala) of the deiodinase 2 (DIO2) enzyme, that converts thyroxine (T4) to triiodothyronine (T3) in the brain, has been identified in about 14% of hypothyroid individuals

Patients with D2 variant had significantly greater symptom improvement with combined LT4/LT3 therapy

McDermott, ME. Endocr Pract. 2012 May 1:1-30. Epub ahead of print

Now with Genomics it is Clear that Some Patients May Benefit Significantly From T3

The Brain Requires Free T3 for Optimal Function. Decreased Genetic Ability to Convert T4 to T3

Increases Risk of Depression and Anxiety

Use of FT3 Patients When DIO2 Polymorphism Suspected

Genomics (which is not covered by insurance for this) is only way to check for DIO2 variants

However; if patients have residual symptoms on LT4 alone or low heart rate; may be reasonable to try combination LT4/LT3 therapy

Physiological LT4 to LT3 ratio of 10:1 to 14:1 is recommended: Limited options of LT3 available and may use porcine derived combination products if wanting once daily (or compound)

Monitor TSH with goal .5-2.5 for most women

Benefit Has Also Been Shown to Using Liothyronine in Depression

Augmentation with Liothyronine has been shown to be beneficial in resistant depression (not dependent on baseline TSH, but more likely to help in those with low starting LT3)

Daily doses were on average 25-37.5 ucg (divide for bid dosing) which is equivalent to 100-125 ucg LT4 so monitor for hyperthyroidism

Iosifescu, D. J of Family Practice; Vol. 5, No. 7 / July 2006

How Do You Respond to the Many Individuals Who Prefer Combo Therapy?

Porcine derived combination products have a strong following

Some people report just “feeling better” when on liothyronine (LT3) with their levothyroxine (LT4)

How do you address this in your practice?

No Set Evidence-based Way to Address at this Time:

Baseline measuring of T3 not that helpful at identifying those who might benefit as different tissues convert differently (i.e. serum may not match)

Eventually, will be widely available to check for DIO2 polymorphism (but not yet)

Personal physician preference – “Turf or Try?” Clinical markers such as residual low heart rate or loss of

lateral 1/3 of eyebrows in someone whose TSH is now “normal” can be helpful

Conversion: 1 Grain is 65-100 ucg Levothyroxine

¼ Grain (16.25 mg)9.5 mcg T4, 2.25 mcg T3

1 Grain (65 mg)38 mcg T4, 9 mcg T3

1 ½ Grain (97.5 mg)57 mcg T4, 13.5 mcg T3

Other option of desiccated thyroid comes in 15 mg, 60 mg, 90 mg (1/4 grain, 1 grain, 1.5 grains)

1 ucg T3 = 3-7 ugT4

Treatment Goals: What is Ideal TSH Goal?

What is Ideal TSH Treatment Goal?

Lab slips generally list .4-4.5 as “normal” TSH, HOWEVER: Women tend to feel better with a TSH closer to

1 (range .5-2.5) hs-crp, endothelial function and homocysteine

levels are better with TSH of .5-2.5

Target TSH for Ideal CardiacFunction Appears to Be <2

Endothelium-dependent vasodilatation correlates inversely with TSH TSH 0.4–2 μIU/mL (11.8 ± 2.7) TSH 2.01-4 μIU/mL (6.8 ± 2.9%), TSH 4.01-10 μIU/mL (5.2 ± 6.3%) TSH >10 μIU/mL (4.0 ± 4.4%)

Endothelial dysfunction (an early step of atherosclerosis) is measurable in patients with subclinical hypothyroidism and corrected with T4Alibaz Oner, F. et al. Endocrine. Vol 40 #2 (2011), 280-284Lekakis, J. Et al. Thyroid. 7(3):411-414 Volume: 7 Issue 3: February 3, 2009

Thyroid Hormone and The Heart

Thyroid Hormone effects: Inflammation Lipid Metabolism Endothelial

Dysfunction Heart Rate Heart Failure Stenosis

Further Info on Ideal TSH

hs-crp and Homocysteine also correlate inversely with TSH with ideal at TSH< 2 Many countries treat to a normal

of TSH .5-2 (India for example)

Drugs: 2012 Jan 1;72(1):17-33

Treating Women to a Lower TSH Expert recommendations have encouraged physicians

to treat women to a TSH of .5-1.5 in US as well for subclinical and overt hypothyroidism

Reasoning relates to preventing: Poor outcomes of pregnancy Dyslipidemias Atherogenesis Increased mortality Symptoms of hypothyroidism

Wartofsky et al; Obstetrical & Gynecological Survey: August 2006 – Volume 61 – Issue 8 – pp 535-542

Treating Women and Elderly…

Thin women often need more LT4 than heavier women Caution in elderly (especially >85) due to

increased risk of Afib, CHF and osteoporosis if you over treat (go slow)

Drugs: 2012 Jan 1;72(1):17-33

Which of the following are TRUE…1. Free T4 is more accurate than T4 for diagnosing

hypothyroidism2. Many countries consider an ideal TSH for women

to be .5-23. Heavier women need more LT4 than thin4. 1 and 25. All of the above

Management of Hypothyroidism

in Pregnancy

Thyroid hormone is essential for fetal brain development, thus

TSH should be kept in lower ideal range during pregnancy (.5-2.0; 2.5 max)

There is a correlation between untreated (or not fully treated) maternal hypothyroidism and neuropsychological impairment in the offspring

Particularly important for fetal well-being and brain development during early first trimester

The Thyroid and Pregnancy

HCG Can Act Like TSH

Human Chorionic Gonadotropin (hCG) has a thyroid stimulating hormone (TSH)-like effect, high hCG concentrations are associated with thyroid stimulation

TSH levels may be suppressed during first trimester of pregnancy as normal finding due to above – check free T4 (normal if fT4 not high)

What is "Normal" TSH in Pregnancy?

Internationally adopted pregnancy reference ranges define hypothyroidism as TSH > or = 2.6 mlU/L

Using this reference 67 of 322 (20.8%) women were diagnosed with sub-clinical hypothyroidism. When typical laboratory criteria were applied TSH > or = 4.6 mlU/L the prevalence dropped to 4.3%

Fetal development is improved with treating to a lower TSH – REFER OR DO THIS

East Mediterr Health J. 2012 Feb;18(2):132-6

Monitoring Thyroid Functions During Pregnancy

TSH levels in hypothyroid women planning pregnancy should be kept at 2.5 mU/L or less (.5-2.5 is ideal)

Within 30-40 days of pregnancy check free T4 TSH checked every 8-12 weeks as needs increase

during pregnancy Typical thyroxine replacement doses increase 25-

50% during pregnancyBritish Columbia Ministry of Health Services; Guidelines and Protocols; Thyroid Function Tests. Effective 1/1/2010

The Thyroid During the PostPartum Period

After delivery most hypothyroid women need a decrease in thyroxine dose back to pre-pregnancy levels

Post-Partum Thyroiditis (where patients make antithyroid peroxidase antibodies) is common (5-10% of women)

This can trigger temporary hyperthyroidism (or not) followed by hypothyroidism

http://nyp.org/health/endocrin-postpart.html

Long-term Monitoring

Follow TSH yearly in patients who had an episode of postpartum thyroiditis even if TSH normalizes Can revert to hypothyroidism 5-10 yrs later

Sarah is planning a pregnancy. She has a history of 1 miscarriage at 6 weeks. Her TSH is 3.5 on levothyroxine (LT4) 88 ucg. You should…

1. Increase her LT4 to 100 ucg and recheck levels in 8 weeks

2. Leave her LT4 dose the same if clinically feeling well

3. Decrease her LT4 dose to 75 ucg

4. Add 5 ucg of LT3 twice a day

Identify a diversity of tissues compartments in which hypothyroidism is

consequential

Actions of Thyroid Hormone

Regulation of carbohydrate, lipid, and protein metabolism

Central nervous system activity and brain development

Cardiovascular stimulation

Bone and tissue growth and development

Gastrointestinal regulation

Sexual maturation

Overall Metabolism: Weight Gain, Cold Intolerance

Neurological: Lethargy, Cognitive Impairment, Depression

Gynecological: Menorrhagia

GI: Constipation

Dermatological: Hair loss, Dry Skin

Other: Goiter

Thyroid Dysfunction Effects Many Body Systems

Hypothyroidism and Lipids

Higher levels of TSH are associated with non favorable lipid profile No lower limit to this correlation

Effect is modest though (typical lipid profile improves about 5% with treatment)

Duntas, LH. et al. Med Clin North Am. 2012 Mar;96(2):269-81. Epub 2012 Feb 14

Hypothyroidism Adversely Effects the Heart

Hypothyroidism has negative effects on the muscles of heart (myocardium) and vasculature that also effect cardiac risk Pumping ability of heart

Vasodilatation

Duntas, LH. et al. Med Clin North Am. 2012 Mar;96(2):269-81. Epub 2012 Feb 14

Cardiac Outcomes and Treatment of Mild Hypothyroidism

Retrospective study done in UK alluded to significant cardiac benefits to treating even mild/subclinical hypothyroidism in 3,000 patients 40-70 yrs old. TSH was 5-10. Incidence of cardiac disease was 4.2 vs. 6% in treated vs.

untreated (HR, 0.61; 95% CI, 0.39-0.95) In seniors (>70) NO relative risk reduction in cardiac

outcomes was seen with subclinical hypothyroidism (HR .99) (1,000 patients)

Arch Intern Med. 2012 Apr 23

Hypothyroidism and Carbohydrate Metabolism

Hypothyroidism decreases proinsulin gene expression in beta cells

Hypothyroidism thus can compound problems with carbohydrate metabolism

Half of patients with Hashimoto’s thyroiditis develop carbohydrate metabolism issues. Part is due to autoimmune issues (antibodies) but part

due to glucose tolerance issues on beta cell level from hypothyroidism

Braz J Med Biol Res. 2011 Oct;44(10):1060-7. Epub 2011 Sep 16

Metformin Suppresses TSH

Women given 1700 mg metformin daily for 3 months had significant lowering of TSH Basal TSH of 3.11 +/- .50 vs. post treatment TSH 1.18 +/-

0.36 (P = 0.01) Mean TSH 3 months after metformin withdrawal went back

up and was not different from basal TSH

CHECK TSH WHEN CHECKING HgA1Cs on your Metformin patients at least with dose changes!

Endocrine. 2007 Aug;32(1):79-82. Epub 2007 Oct 2

Thyroid and Bone Metabolism

Subclinical or Overt Hyperthyroidism increases bone loss and is a cause of secondary osteoporosis

Untreated hypothyroidism in children/ teens will cause short stature, The deficit in adult stature correlates to the duration of untreated hypothyroidism (P < 0.01) Bottom line screen children and teens with symptoms

of hypothyroidism

N Engl J Med. 1988 Mar 10;318(10):599-602

Hypothyroidism and Gut Issues Decreased motility leads to constipation Hashimoto’s Thyroiditis (most common cause of hypothyroidism)

affects gut Esophageal Motility Disorder Dysphagia Heartburn

Delayed Gastric Emptying Nausea, Vomiting Dyspepsia

Autoimmune gastritis – low acid/gastrin Bacterial overgrowth and bloating

Ebert, EC et al. J Clin Gastroenterol. 2010 Jul;44(6):402-6.

Hypothyroidism and Sexual Maturation and Function

T3 acts directly on the testes Effects Sertoli and Leydig cell

proliferation, testicular maturation, and steroidogenesis

Normal thyroid function is essential for normal function of the gonadal axis Hypothyroidism will cause

oligomenorrhea and menorrhagia

Which of the following are false?1. Thyroid hormone is involved in testicular function and

synthesis of hormones2. Lipid levels are likely to decrease about 50% with treatment

of hypothyroidism3. Heartburn and other upper GI symptoms can be triggered

by Hashimoto’s 4. Metformin can lower TSH5. Untreated hypothyroidism in children can cause short

stature

Thank You!Sharon Hausman-Cohen, MD

sharon.md@resilienthealthaustin.com