Evidence Based Management of Hypothyroidism in Primary Care

Transcription

1 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

2 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 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 First A Brief Review A CLOSER LOOK AT THYROID HORMONES BIOSYNTHESIS OF THYROID HORMONES: WHAT IS THYROID HORMONE 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 1

3 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) 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) WHAT ABOUT FREE T3 AND FREE T4? Only 0.03 % of T 4 and 0.3 %of T 3 are not bound to proteins; free T 4 (FT 4 ) and free T 3 (FT 3 ) FT 3 /FT 4 are the physiologically active thyroid hormones T 3 (liothyronine) is 3 4x more potent than T 4 (levothyroxine). T 3 is more active because it is not as tightly bound to serum proteins as T 4, 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 T 4 and sometimes Free T 3 are useful for confirmation Total T 3 /T 4 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 T 3 and T 4 ordered with Free T 3 and Free T 4! Reason for ordering T 3 / T 4 over free hormone levels in the 1990s and before was due to cost of determining free hormone levels FT 3 / FT 4 are each about a $5 7 assay now Overt and Subclinical Hypothyroidism: Who to Treat and How 2

4 OVERT HYPOTHYROIDISM (PRIMARY HYPOTHYROIDISM): Plasma TSH is : Plasma Total T 4 : (but don t order) Plasma Free T 4 : Plasma free T 3 and total T 3 measurements are of no value here, since normal concentrations are often observed SUBCLINICAL PRIMARY HYPOTHYROIDISM: Plasma TSH: High Thyroid hormone levels (ft 4 ): 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 T 3 and free T 4 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 Lab slips generally list 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 During pregnancy, there is excellent evidence for keeping TSH in this lower ideal TARGET TSH FOR IDEAL CARDIAC FUNCTION APPEARS TO BE <2: Endothelium dependent vasodilatation correlates inversely with TSH TSH μiu/ml (11.8 ±2.7) TSH μiu/ml (6.8 ±2.9%), TSH 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 T 4 Alibaz Oner, F. et al. Endocrine Vol 40 #2 (2011), Lekakis, J. Et al. Thyroid 7(3): Volume: 7 Issue 3: February 3,

5 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 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 Wartofsky et al; Obstetrical & Gynecological Survey: August 2006, Volume 61, Issue 8, pp TREATING WOMEN AND ELDERLY Thin women often need more LT 4 than heavier women Caution in elderly (especially >85) due to increased risk of Afib, CHF and osteoporosis if you over treat (go slow) IS THERE A BENEFIT TO USING COMBINATION THYROID THERAPY? Most Trials of T 4 and LT 3 combined vs. T 4 alone have been small and no clear benefit in overall populations using combination vs. T 4 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 Drugs: 2012 Jan 1;72(1):17 33 Valizadeh, M. et al. Endocr Res. 2009;34(3):80 9. Escobar Morreale et al. J Clin Endocrinol Metab Aug;90(8): Epub 2005 May 31 SUBSET OF PATIENTS MAY RELATE TO GENE VARIANT (POLYMORPHISM) Overall no clinical benefit was seen using combination LT 4 /LT 3 HOWEVER: A polymorphism (Thr92Ala) of the deiodinase 2 (D2) enzyme, that converts thyroxine (T 4 ) to triiodothyronine (T 3 ) in the brain, was later identified in about 16% of hypothyroid individuals Patients with D2 variant had significantly greater symptom improvement with combined LT 4 /LT 3 therapy USE OF LT3 PATIENTS WHEN D2 POLYMORPHISM SUSPECTED Currently no commercially available way to check for D2 enzyme When patients have residual symptoms on LT 4 alone; may be reasonable to try combination LT 4 /LT 3 therapy When used, a physiological LT 4 to LT 3 ratio of about 10:1 to 14:1 is recommended although limited options of LT 3 available Serum TSH should be monitored to ensure that euthyroidism is maintained McDermott, ME. Endocr Pract May 1:1 30. Epub ahead of print 4

6 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 LT 3 ) Daily doses were on average ucg which is equivalent to ucg LT 4 so monitor for hyperthyroidism HOW DO YOU RESPOND TO THE MANY INDIVIDUALS WHO PREFER COMBO THERAPY? 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 (LT 3 ) with their levothyroxine (LT 4 ) 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 T 3 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. Which of the following are TRUE 1. Free T 4 is more accurate than T 4 for diagnosing hypothyroidism 2. Many countries consider an ideal TSH for women to be Heavier women need more LT 4 than thin 4. 1 and 2 5. All of the above Management of Hypothyroidism in Pregnancy 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 5

7 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 T 4 (normal if ft 4 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 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 ( is ideal) Within days of pregnancy check free T 4 TSH checked every 8 12 weeks as needs increase during pregnancy Typical thyroxine replacement doses increase 25 50% during pregnancy THE THYROID DURING THE POST PARTUM PERIOD: After delivery, most hypothyroid women need a decrease in thyroxine dose back to prepregnancy 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 (LT 4 ) 88 ucg. You should 1. Increase her LT 4 to 100 ucg and recheck levels in 8 weeks 2. Leave her LT 4 dose the same if clinically feeling well 3. Decrease her LT 4 dose to 75 ucg 4. Add 5 ucg of LT 3 twice a day 6

8 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 Overall Metabolism: Weight Gain, Cold Intolerance Neurological: Lethargy, Cognitive Impairment, Depression Gynecological: Menorrhagia GI: Constipation Dermatological: Hair loss, Dry Skin Other: Goiter HYPOTHYROIDISM ADVERSELY EFFECTS LIPIDS AND THE HEART 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 Mar;96(2): 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 3000 patients yrs old. TSH was 5 10 Incidence of cardiac disease was 4.2 vs. 6% in treated vs. untreated (HR, 0.61; 95% CI, ) In seniors (>70) NO relative risk reduction in cardiac outcomes was seen with subclinical hypothyroidism (HR.99) (1000 patients) 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 Arch Intern Med Apr 23 Braz J Med Biol Res Oct;44(10): Epub 2011 Sep 16 7

9 METFORMIN SUPPRESSES TSH Women given 1700 mg metformin daily for 3 months had significant lowering of TSH Basal TSH of /.50 vs post treatment TSH / 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): Epub 2007 Oct 2 N Engl J Med Mar 10;318(10): 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 HYPOTHYROIDISM AND SEXUAL MATURATION AND FUNCTION T 3 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 Ebert, EC et al. J Clin Gastroenterol Jul;44(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 8

10 AMIODARONE AND HYPOTHYROIDISM Amiodarone is an iodine rich compound that has a structure similar to T 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 T 4 T 3, so T 4 and rt 3 increase, but T 3 which is more biologically active decreases 20 25% Amiodarone can also effect the ability for T 4 and T 3 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; DO NOT EMPIRICALLY TREAT TSH IN PATIENTS ON AMIODARONE Check not only TSH but also free T 4 and free T 3 (or T 4 and T 3 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 T 4 increases (enough to compensate for low T 3 ) 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) 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 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; 9

11 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 FT 4 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 10

12 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

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