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Sunday General Session Evidence‐Based Management of Hypothyroidism in Primary Care Sharon Hausman‐Cohen, MD Family Medicine, Private Practice Balcones Woods Family Medicine Diplomate, American Board of Integrative Medicine and American Board of Family Medicine Austin, Texas Educational Objectives By the end of this activity, the participant should be better able to: 1. Develop a screening protocol to identify patients with risk factors for developing hypothyroidism, order appropriate laboratory tests to diagnose hypothyroidism, and diagnose subclinical hypothyroidism. 2. Prescribe appropriate pharmacotherapy for patients with hypothyroidism and monitor patients accordingly. 3. Identify a diversity of tissue compartments in which hypothyroidism is consequential. Speaker Disclosure Dr. Hausman‐Cohen has disclosed that she has no actual or potential conflict of interest in relation to this topic. 20 SPEAKER DISCLOSURE
HYPOTHYROIDISM: TREATING TO OPTIMAL LEVELS
• Dr. Hausman‐Cohen has disclosed that she has no actual or potential conflict of interest in relation to this topic.
2016 Texas Family Medicine Symposium
Sharon Hausman‐Cohen, MD
Austin, TX
LEARNING OBJECTIVES
By the end of this activity, the participant will be better able to:
• Develop a screening protocol to identify patients with risk factors for developing hypothyroidism, order appropriate laboratory tests to diagnose hypothyroidism, and diagnose subclinical hypothyroidism.
• Prescribe appropriate pharmacotherapy for patients with hypothyroidism and monitor patients accordingly.
• Identify a diversity of tissue compartments in which hypothyroidism is consequential.
TOPICS COVERED
• Overt and subclinical hypothyroidism: Who to treat and how
• Management of hypothyroidism in pregnancy
• Hypothyroidism and its relationship to other systems such as heart, bones, and brain
• Incidence of hypothyroidism in special populations; patients on lithium and amiodarone
BIOSYNTHESIS OF THYROID HORMONES: WHAT IS THYROID HORMONE
First A Brief Review
A CLOSER LOOK AT THYROID HORMONES
• Iodine is a key in the biosynthesis
• Thyroglobulin acts as a matrix to holding the iodine as it attaches to tyrosine
• Building blocks: Monoiodotyrosine (MIT) and diiodotyrosine (DIT)
• The coupling of two DIT molecules forms T4
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T3 AND REVERSE T3 – WHAT ARE THEY?
T3 AND REVERSE T3 – WHAT ARE THEY?
• The coupling of one DIT molecules and one MIT molecule results in the formation of T3 or reverse T3
(rT3) • Almost all circulating T4 and T3 hormones are bound to serum proteins (thyroid hormone‐binding proteins)
• The coupling of one DIT molecules and one MIT molecule results in the formation of T3 or reverse T3
(rT3) • Almost all circulating T4 and T3 hormones are bound to serum proteins (thyroid hormone‐binding proteins)
WHAT ABOUT FREE T3 AND FREE T4?
• Only 0.03 % of T4 and 0.3 % of T3 are not bound to proteins; free T4 (FT4) and free T3
(FT3)
• FT3/FT4 are the physiologically active thyroid hormones
• T3 (liothyronine) is 3‐4x more potent than T4
(levothyroxine). T3 is more active because it is not as tightly bound to serum proteins as T4, and has a greater affinity to target tissue receptors
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
• Total T3/T4 not as useful. 99% of thyroid hormone is protein bound and pregnancy and other factors effect total levels
AFRAID TO STOP ORDERING T3 AND T4?
• In British Columbia, labs have standing orders to replace any T3 and T4 ordered with Free T3
and Free T4! • Reason for ordering T3/ T4 over free hormone levels in the 1990s and before was due to cost of determining free hormone levels
• FT3/ FT4 are each about a $5‐7 assay now
Overt and Subclinical Hypothyroidism: Who to Treat and How
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OVERT HYPOTHYROIDISM (PRIMARY HYPOTHYROIDISM):
• Plasma TSH is : ↑ • Plasma Total T4: ↓ (but don’t order)
• Plasma Free T4: ↓
• Plasma free T3 and total T3 measurements are of no value here, since normal concentrations are often observed
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
Before
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
WHAT IS IDEAL TSH TREATMENT GOAL
TARGET TSH FOR IDEAL CARDIAC FUNCTION APPEARS TO BE <2:
• 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
• During pregnancy, there is excellent evidence for keeping TSH in this lower ideal
• Endothelium‐dependent vasodilatation correlates inversely with TSH
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•
•
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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 T4
Alibaz Oner, F. et al. Endocrine Vol 40 #2 (2011), 280‐284
Lekakis, J. Et al. Thyroid ‐ 7(3):411‐414 Volume: 7 Issue 3: February 3, 2009
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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)
TREATING WOMEN TO A LOWER TSH
• Expert recommendations have encouraged physicians to treat women to a TSH of .5‐1.5 in U.S. as well for subclinical and overt hypothyroidism
• Reasoning relates to preventing:
• Poor outcomes of pregnancy • Dyslipidemia
• Atherogenesis
• Increased mortality
• Symptoms of hypothyroidism
Drugs: 2012 Jan 1;72(1):17‐33
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
Wartofsky et al; Obstetrical & Gynecological Survey: August 2006, Volume 61, Issue 8, pp 535‐542
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 overall populations 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
SUBSET OF PATIENTS MAY RELATE TO GENE VARIANT (POLYMORPHISM)
USE OF LT3 PATIENTS WHEN D2 POLYMORPHISM SUSPECTED
• Overall no clinical benefit was seen using combination LT4/LT3 HOWEVER:
• A polymorphism (Thr92Ala) of the deiodinase 2 (D2) enzyme, that converts thyroxine (T4) to triiodothyronine (T3) in the brain, was later identified in about 16% of hypothyroid individuals
• Patients with D2 variant had significantly greater symptom improvement with combined LT4/LT3 therapy
• Currently no commercially available way to check for D2 enzyme
• When patients have residual symptoms on LT4 alone; may be reasonable to try combination LT4/LT3
therapy
• When used, a physiological LT4 to LT3 ratio of about 10:1 to 14:1 is recommended although limited options of LT3 available
• Serum TSH should be monitored to ensure that euthyroidism is maintained
McDermott, ME. Endocr Pract. 2012 May 1:1‐30. Epub ahead of print
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BENEFIT HAS ALSO BEEN SHOWN TO USING LIOTHYRONINE IN DEPRESSION
HOW DO YOU RESPOND TO THE MANY INDIVIDUALS WHO PREFER COMBO THERAPY?
• 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 which is equivalent to 100‐125 ucg LT4 so monitor for hyperthyroidism
• Armour thyroid, Nature Thyroid and other combination products (porcine origin) exist and 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?
Iosifescu, D. J of Family Practice; Vol. 5, No. 7 / July 2006
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)
• Can’t check for D2 polymorphism (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.
Management of Hypothyroidism in Pregnancy
Which of the following are TRUE…
1. Free T4 is more accurate than T4 for diagnosing hypothyroidism
2. Many countries consider an ideal TSH for women to be .5‐2
3. Heavier women need more LT4 than thin
4. 1 and 2
5. All of the above
• Thyroid hormone is essential for fetal brain development, thus TSH should be kept in ideal range during pregnancy
• There is a correlation between untreated (or not fully treated) maternal hypothyroidism and neuropsychological impairment in the offspring
• Proper thyroid hormone levels are particularly important for fetal well being and brain development during early first trimester
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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
THE THYROID DURING THE POST PARTUM PERIOD:
• 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 pregnancy
• After delivery, most hypothyroid women need a decrease in thyroxine dose back to pre‐
pregnancy levels
• Post Partum Thyroiditis (where patients make anti‐thyroid peroxidase antibodies) is common (5‐10% of women).
• This can trigger temporary hyperthyroidism (or not) followed by hypothyroidism
British Columbia Ministry of Health Services; Guidelines and Protocols; Thyroid Function Tests. Effective 1/1/2010
LONG‐TERM MONITORING:
• Follow TSH yearly in patients who had an episode of post partum 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
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ACTIONS OF THYROID HORMONE Hypothyroidism and its relationship to other systems such as heart, bones, and brain
• 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 THYROID DYSFUNCTION THUS AFFECTS MANY BODILY SYSTEMS
HYPOTHYROIDISM ADVERSELY EFFECTS LIPIDS AND THE HEART
• Overall Metabolism: Weight Gain, Cold Intolerance
• Neurological: Lethargy, Cognitive Impairment, Depression
• Gynecological: Menorrhagia
• GI: Constipation
• Dermatological: Hair loss, Dry Skin
• Other: Goiter • 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)
• 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
HYPOTHYROIDISM AND CARBOHYDRATE METABOLISM
• Retrospective Study Done in UK alluded to significant cardiac benefits to treating even mild/subclinical hypothyroidism in 3000 patients 40‐70 yrs old. TSH was 5‐10
• 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
• 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) (1000 patients)
Arch Intern Med. 2012 Apr 23
• 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
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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
HYPOTHYROIDISM 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
Endocrine.2007 Aug;32(1):79‐82. Epub 2007 Oct 2
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 N Engl J Med. 1988 Mar 10;318(10):599‐602
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
• Autoimmune gastritis – low acid/gastrin • Bacterial overgrowth and bloating
Ebert, EC et al. J Clin Gastroenterol. 2010 Jul;44(6):402‐6. Which of the following is false?
1. Thyroid hormone is involved in testicular function and synthesis of hormones
2. Lipid levels are likely to decrease about 50% with treatment of hypothyroidism
3. Heartburn and other upper GI symptoms can be triggered by Hashimoto’s 4. Metformin can lower TSH
5. Untreated hypothyroidism in children can cause short stature
Lithium and Amiodarone…. Special case to be aware of.
Hypothyroidism In Individuals on Specific Medications
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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
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?
Gopalan, M. et al. Thyroid Dysfunction Induced by Amiodarone; www.emedicine.medscape.com/article/ 129033
DO NOT EMPIRICALLY TREAT TSH IN PATIENTS ON AMIODARONE
• Check not only TSH but also free T4 and free T3 (or T4
and T3 if need be since hormone binding globulin not effected) before treating
• 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
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
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)
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
Sarlis, N. et al. Lithium Induced Goiter; http://emedicine.medscape.com/article/120243 9
FOLLOWING LITHIUM PATIENTS WITH THYROID LABORATORY TESTS
• 3 months after starting lithium it is recommended to check TSH, anti‐TPO (thyroid peroxidase ab) and Antithyroglobulin
• 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
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
THANK YOU!
SHARON HAUSMAN‐COHEN, MD
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Medication Index
Evidence‐Based Management of Hypothyroidism in Primary Care
The following medications were discussed in this presentation. The table below lists the generic and trade name(s) of these medications. Generic Name
Amiodarone
Levothyroxine
Liothyronine
Lithium
Trade Name
Coradone, Nexterone, Pacerone
Levo‐T, Levothroid, Levoxyl, Synthroid, Tirosint, Unithroid
Cytomel, Triostat
Lithobid
Notes