Hypothyroidism and Hyperthyroidism Paul V. Tomasic, MD, MS, FACP, FACE Nevada AACE EFNE & Annual Meeting October 6, 2018
Disclosures: None related to this program or presentation
Objectives: Hypothyroidism and Hyperthyroidism Review the essentials of diagnosing and treating hypothyroidism in the primary care setting and when to refer to an endocrinologist. Discuss conditions of special significance in hypothyroidism, such as pregnancy. Review the essentials of diagnosing and treating hyperthyroidism in the primary care setting and when to refer to an endocrinologist. Discuss the approach to treating special circumstances in hyperthyroidism, such as pregnancy, and the approach to treating drug-associated thyrotoxicosis.
Clinical Practice Guidelines for Hypothyroidism in Adults: AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN THYROID ASSOCIATION 2012 Garber JR et al. Thyroid December 2012 Endocrine Practice November-December 2012
Percentage of Euthyroid, Subclinical and Hypothyroid Patients Reporting Symptoms 60% euthyroid have 1 symptom 15% 4 symptoms R5. Clinical scoring systems should not be used to diagnose hypothyroidism. Grade A, BEL 1 Canaris et al.
Primary: Principal Cause and Largely Autoimmune Postradioiodine and Postsurgical Central Causes of Hypothyroidism Secondary + Tertiary More recently recognized etiologies Chemotherapeutic Agents Ipilimumab, Bexarotene, Sunitinib (tyrosine kinase inhibitors) Consumptive hypothyroidism
Severity of Primary Hypothyroidism by Thyroid Levels TSH rises first and abruptly Decline of T4 and T3 slower and later
Hypothyroidism Subclinical Normal Free T4 Estimate Overt Low Free T4 Estimate TSH usually below 10 TSH usually above 10 5% or more USA Less than 1% USA
TSH an excellent test except some pitfalls Central disease Abnormal isoforms, TSH receptor polymorphisms Drugs (glucocorticoids, dopaminergic drugs) Diurnal Variation Heterophilic antibodies--particularly low titer Requires steady state: pitfalls in an inpatient population and early phases of pregnancy Adrenal Insufficiency (may raise TSH)
TSH Population Reference Range Reasons for the skew BESIDES AGE Euthyroid Outliers - inherent TSH lability Measurement of bioinactive TSH isoforms TSH receptor polymorphisms - TSH sensitivity Occult autoimmune thyroid dysfunction (AITD) 95% Limits 0.3-0.4 1.3-1.4 2.5-3.0 ~ 4-5 10 TSH miu/l
Normal range of TSH values? R14.1 The reference range of a given laboratory should determine the upper limit of normal for a third generation TSH assay. TSH levels may rise with age. If an age based upper limit of normal for a third generation TSH assay is not available in an iodine sufficient area, an upper limit of normal of 4.12 should be considered. Grade A, BEL 1. Hollowell JG et al. 2002 JCEM 87:489-99 (EL1). Hamilton TE et al. 2008 JCEM 93:1224-30 (EL1). Boucai L et al. 2011 Thyroid 21:5-11(EL1)
Principal Lab Tests to Diagnose and Monitor Hypothyroidism Free Hormone Hypothesis Only free hormone metabolically active and determines thyroid status (not total which is largely bound to binding proteins) Gold standard: Equilibrium Dialysis Estimates Free Thyroxine Assays - Use anti T4 Antibodies Free Thyroxine Index = Total T4 x T3 UPTAKE T3 Uptake ESTIMATES % free hormone
Serum T3 Level Should not be Used to Diagnose Hypothyroidism R10. Serum total T3 or assessment of serum free T3 should not be done to diagnose hypothyroidism Grade A, BEL 2; Upgraded because of many independent lines of evidence and expert opinion.
Anti-Thyroid Antibodies Markers of Chronic Thyroiditis Anti- Thyroglobulin Antibodies Do not correlate with hypothyroidism Anti-Thyroid Peroxidase Antibodies (formerly known as Anti-microsomal Antibodies) Correlate with the development of hypothyroidism
Anti- TSH Receptor Antibodies TSHRAb Used in the diagnosis and monitoring of Graves TSI (Thyroid Stimulating Immunoglobulin) TBII (TSH Binding Inhibitory Immunoglobulin)
When Should Antithyroid Antibodies Be Measured? R1.Thyroid peroxidase antibody (TPOAb) measurement should be considered when evaluating patients with subclinical hypothyroidism. Grade B, BEL 1; Downgraded. If positive, hypothyroidism rate of 4.3% versus 2.6% per year. Therefore, may or may not influence the decision to treat.
Pregnancy Thyroid Testing Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in 1st trimester provides strong physiological evidence to support redefining TSH upper limit of normal in 1 st trimester to 2.5 miu/liter. R9. In pregnancy, the measurement of total T4 or a free thyroxine index (FTI), in addition to TSH, should be done to assess thyroid status. Because of the wide variation in the results of free T4 assays, should only use when methodspecific and trimester-specific reference ranges are available. Grade B, BEL 2 Negro, J Clin Endocrinol Metab. 2010 Sep;95(9)
Pregnancy normal-range TSH values R. 14.2 In pregnancy, the upper limit of the normal range should be based on trimester-specific ranges for that laboratory. If trimester-specific reference ranges for TSH are not available in the laboratory, the following upper normal reference ranges are recommended: first trimester, 2.5 miu /L; second trimester,3.0 miu/l; third trimester, 3.5 miu/l. Grade B, BEL 2.
Treatment prior to Pregnancy R19. Treatment with L-thyroxine should be considered in women of child bearing age with serum TSH levels between 2.5 miu/l and the upper limit of normal for a given laboratory s reference range if they are in the first trimester of pregnancy or planning a pregnancy including assisted reproduction in the near future. Grade B, BEL 2
Screening During Pregnancy? R20.1.1 Universal screening is not recommended for patients who are pregnant or are planning pregnancy, including assisted reproduction. Grade B, BEL 1; limitations to evidence and therefore insufficient evidence for lack of benefit to recommend Grade A Teng W & Shan Z 2011 Thyroid 21:1053-55 (EL4). Li Y et al. 2010 Clin Endo 72:825-29 (EL2). Haddow JE et al. 1999 NEJM 341:549-55 (EL2). Yu X et al. 2010-1037 ITC Paris (EL2). Lazarus JH et al. 2012 NEJM 366:493-501 (EL1). Negro R et al. 2006 JCEM :2587-2591 (EL2). Kim CH et al. 2011 Fertil Steril 95:1650-54 (EL2).
Role for TPOAb? R3. TPOAb measurement should be considered when evaluating patients with infertility, particularly recurrent miscarriage. Grade A, BEL 2; upgraded because of favorable risk-benefit potential.
Treatment of TPOAb+ Women? R19.2 Treatment with L-thyroxine should be considered in women of child-bearing age with normal thyroid hormone levels when they are pregnant or planning a pregnancy including assisted reproduction if they have or have had positive levels of serum TPOAb, particularly when there is a history of miscarriage or past history of hypothyroidism Grade B, BEL 2
Impact of treatment with LT4 on TPO Ab (+) Pregnancy Negro et al 2006
Thyroid hormone should not be used to treat obesity R30. Thyroid hormone should not be used to treat obesity in euthyroid patients. Grade A, BEL 2 Upgraded to A because of potential harm inconclusive benefit and induces subclinical hyperthyroidism
Value of Treating Patients with TSH Values Between 2.5 and 4.5 No prospective study has shown TSH levels lower than 4.5 to 10 are associated with more cardiovascular disease Pregnancy outcomes notable exception Many who do are mild, at low risk for progression, and may even remit The risk of overtreatment is not trivial (approximately 20%) Surks MI, et al. J Clin Endocrinol Metab. 2005;90:5489-96. Walsh JP, et al. J Clin Endocrinol Metab. 2006;91:2624-30.
Hazards of Overtreatment Heart, Bone, Psychiatric High risk subclinical hyperthyroid in patients on thyroid medication Colorado Prevalence Study, 2000 20.7% (316) of patients on thyroid medication had subclinical hyperthyroidism 0.9% (13) Overt hyperthyroidism More adverse effects with poor monitoring Only 56% received standard monitoring Atrial fibrillation, unstable angina with poor monitoring Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. Stelfox HT, et al. J Eval Clin Pract. 2004;10:525-30.
Treatment of TSH between 5 and 10? Depends R16. Treatment should be considered particularly if they have symptoms suggestive of hypothyroidism, positive TPO antibodies or evidence of atherosclerotic cardiovascular disease, heart failure or have associated risk factors for these diseases. Grade B, BEL 1; evidence not fully generalizable to stated recommendation and there are no prospective, interventional studies. Vanderpump MP et al. 1995 Clin Endo 43:55-68 (EL2). Vanderpump MP & Tunbridge WM 2002 Thyroid 12:839-47 (EL4). Hollowell JG et al. 2002 JCEM 87:489-99 (EL1). Huber G et al. 2002 JCEM 87:3221-26 (EL2). McQuade C et al. 2011 Thyroid 21:837-43 (EL3). Ochs N et al. 2008 Ann IM 148:832-45 (EL1).
Treatment of TSH levels > 10 is recommended R15. Patients whose serum TSH levels exceed 10 miu/l are at increased risk for heart failure and cardiovascular mortality, and should be considered for treatment with L-thyroxine. Grade B, BEL 1; not generalizable and meta-analysis does not include prospective interventional studies. Hypothyroid patients treated with normalized TSH are still more likely to feel poorly (Saravan Clinical Endo 2002; Boeving Thyroid 2011) Surks et al. 2004 JAMA 291:228-38 (EL4). Rodondi N et al. 2010 JAMA 304:1365-74 (EL2). Razvi S et al. 2010 JCEM 95:1734-40 (EL3). Gencer B et a.2012 Circulation Epub before print (EL1).
Non-pregnant TSH target goals R17. In patients with hypothyroidism who are not pregnant, the target range should be the normal range of a third generation TSH assay. If an upper limit of normal for a third generation TSH assay is not available, an upper limit of normal of 4.12 should be considered and if a lower limit of normal is not available, 0.45 should be considered. Grade B, BEL 2
Has a Role in the Treatment of Hypothyroidism Been Demonstrated with T3? Endpoints have been mostly affective ones Trials have been relatively short Studies to date mixed and meta-analyses negative, but not completely Combination therapy still not yet completely understood in the setting of patient preferences
L-T4 is the Preferred Treatment R22.1 Patients with hypothyroidism should be treated with L-thyroxine monotherapy Grade A, BEL1. R22.2 Evidence does not support using L-T4 and L-T3 combinations to treat hypothyroidism. Grade B, BEL1. Not considered Grade A because unresolved issues raised by studies reporting some patients prefer and some patient subgroups may benefit from L-T4 and L- T3 combination. Escobar-Morreale HF et al. 2005 JCEM 90:4946-54 (EL4). Grozinsky-Glasberg S et al. 2006 JCEM 91:2592-99 (EL1). Panicker V et al. 2009 JCEM 94:1623-29 (EL3). Applehof BC et al. 2005 JCEM 90:6296-99 (EL3). Clarke N et al. 2004 Treat Endo 3:217-21 (EL4).
LT-4 is Preferred for Treatment in Pregnancy R22.3 L-thyroxine and L-triiodothyronine combinations should not be administered to pregnant women or those planning pregnancy Grade B, BEL 3; upgraded because of potential for harm of hypothyroxinemia during pregnancy Pop VJ et al. 1999 Clin Endo 50:149-55 (EL3). Pop VJ et al. 2003 Clin Endo 59:282-88 (EL3). Kooistra L 2006 Pediatrics 117:161-67 (EL3). Henrichs J et al. 2010 JCEM 95:4227-34 (EL3).
Initiating therapy in overt hypothyroidism Recommendation 22.7.1: When initiating therapy in young healthy adults with overt hypothyroidism, beginning treatment with full replacement doses should be considered (1.6 1.7 mcg/kg). Grade B, BEL 2 Recommendation 22.7.2: When initiating therapy in patients older than 50-60 years old with overt hypothyroidism, without evidence of coronary heart disease, an L-thyroxine dose of 50 mcg daily should be considered. Grade D, BEL 4
Initiating treatment in subclinical hypothyroidism Recommendation 22.8: In patients with subclinical hypothyroidism initial L-thyroxine dosing is generally lower than what is required in the treatment of overt hypothyroidism. A daily dose of 25 to 75 mcg should be considered, depending on degree of TSH elevation. Further adjustments should be guided by clinical response and follow up laboratory determinations including TSH values. Grade B, BEL 2
Question 3.12 How should hypothyroidism be treated and monitored? R23. L-thyroxine should be taken with water consistently 30 to 60 minutes before breakfast or at bedtime 4 hours after the last meal. It should be stored properly per product insert and not taken with substances or medications that interfere with its absorption. Grade B, BEL 2. Bolk N et al. 2010 Arch IM 170:1996-2003 (EL2). Bach-Huynh TG 2009 JCEM 94:3905-12 (EL2.)
Counsel Patients Taking Alternative Therapies About Potential Side Effects and Hazards Supraphysiologic amounts of iodine may alter thyroid status, particularly in those with disease Many thyroid-enhancing products have sympathomimetic amines and iodine Many thyroid support products have significant amount of thyroid hormone R34 Patients should be counseled about the potential side effects of preparations containing iodine sympathomimetic amines thyroid support since they could be adulterated with L-thyroxine or L-triiodothyronine. Grade D BEL 4
HYPERTHYROIDISM AND OTHER CAUSES OF THYROTOXICOSIS: MANAGEMENT GUIDELINES OF THE AMERICAN THYROID ASSOCIATION AND THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS 2011 Bahn RS et al. Endocrine Practice May-June 2011
Thyrotoxicosis associated with a normal or elevated radioiodine uptake over the neck Graves Disease Causes of Hyperthyroidism Toxic adenoma or Toxic multinodular goiter TSH-producing pituitary adenoma Resistance to thyroid hormone (T3 receptor mutation)
Thyrotoxicosis associated with a near-absent radioiodine uptake over the neck Painless (silent) thyroiditis Amiodarone-induced thyroiditis Subacute (granulomatous, de Quervain s) thyroiditis Iatrogenic thyrotoxicosis Factitious ingestion of thyroid hormone Struma ovarii Acute thyroiditis Causes of Hyperthyroidism Extensive metastases from follicular thyroid cancer
Determination of Etiology R1: A radioactive iodine uptake should be performed when the clinical presentation of thyrotoxicosis is not diagnostic of GD; a thyroid scan should be added in the presence of thyroid nodularity In a patient with a symmetrically enlarged thyroid gland, recent onset of ophthalmopathy, and moderate to severe hyperthyroidism, the diagnosis of GD is sufficiently likely
Symptomatic Management R2: Beta-adrenergic blockade should be given to elderly patients with symptomatic thyrotoxicosis and to other thyrotoxic patients with resting heart rates in excess of 90 bpm or coexistent cardiovascular disease R3: Beta-adrenergic blockade should be considered in all patients with symptomatic thyrotoxicosis
How should overt hyperthyroidism due to GD be managed? R4: Patients with overt Graves hyperthyroidism should be managed with any of the the following modalities: 131-I therapy, antithyroid medication, or thyroidectomy
If 131-I is chosen, how should it be accomplished? R5: Patients with GD who are extremely symptomatic or have Free T4 estimates 2-3 times the upper limit normal should be treated with beta-blocker blockade prior to radioactive iodine therapy R6: Pretreatment with methimazole prior to radioactive iodine therapy should be considered in patients at increased risk for complications due to worsening hyperthyroidism
Administration of 131-I in GD R8: Sufficient radiation should be administered in a single dose (typically 10-15 mci) to render the patient with GD hypothyroid R9: A pregnancy test should be obtained within 48 hours prior to treatment in any female with childbearing potential
Patient follow-up after 131-I R11: Follow-up within the first 1-2 months after radioactive iodine therapy for GD should include an assessment of free T4 and total T3. If patient remains thyrotoxic, biochemical monitoring should be considered at 4-6 week intervals R12: When hyperthyroidism persists after 6 months, retreatment with 131-I is suggested
Initiation of antithyroid drug therapy for the treatment of GD R13: Methimazole should be used in virtually every patient who chooses antithyroid drug therapy for GD, except for the first trimester of pregnancy when propylthiouracil is preferred, in the treatment of thyroid storm, and in patients with minor reactions to methimazole who refuse radioactive iodine or surgery R14: Inform patients of side effects of ATDs R15: Check baseline CBC and liver profile
Duration of antithyroid drug therapy for GD R19: Continue for approximately 12-18 months, then tapered or discontinued if the TSH is normal at that time R20: Measurement of TRAb levels prior to stopping antithyroid drug therapy is suggested, as it aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission R11: If no remission: 131-I, surgery, ATDs
If thyroidectomy chosen for GD R22: Render patients euthyroid with methimazole R23: If not rendered euthyroid: treat with betablockade and potassium iodine immediate preoperative period R24: Near-total or total thyroidectomy is the procedure of choice R25: Refer to a high-volume surgeon
Postoperative care R26: following thyroidectomy, serum calcium and intact parathyroid hormone levels should be measured R27 Antithyroid drugs stopped at the time of thyroidectomy and beta-blockers weaned following surgery R28: start levothyroxine at a daily dose appropriate for weight (1.6-1.7 mcg/kg)
Diagnosis of hyperthyroidism in pregnancy R68: Diagnosis made using serum TSH values, and either total T4 and T3 with total T4 and T3 reference range adjusted at 1.5 times the nonpregnant range or free T4 and free T3 estimations with trimester-specific normal reference ranges R69: Transient hcg-mediated thyrotropin suppression in early pregnancy should not be treated with antithyroid drug therapy
TSH is Lower Particularly in 1st trimester Free T4 in pregnancy unreliable weeks gestation 10 20 30 40 +100 E2 hcg TBG +50 TT4 % Change vs. Non-pregnant 0 TSH FT4-50 1st. Trimester 2nd. Trimester 3rd. Trimester
1 st TRIMESTER TSH NORMS TSH Upper Limit 5 ~ 2.5 1 2.3 2.7 2.5 TSH miu/l A B C 0.1 0.03 ~ 0.02 0.02 0.01 95% reference limits A n = 343 (Hong Kong) Panesar et al Ann Clin Biochem 38:329, 2001 B n = 17,298 (USA) Casey et al Obstet Gynecol 105:239, 2005 C n = 115 Mestman (USA) ITC, Buenos Aires, Argentina, 10/2005
Management of hyperthyroidism in pregnancy R70: Antithyroid drug therapy should be used for hyperthyroidism due to GD that requires treatment during pregnancy. Propylthiouracil should be used when antithyroid drug therapy is started during the first trimester. Methimazole should be used when antithyroid drug therapy is started after the first trimester
Management of hyperthyroidism in pregnancy R72: GD during pregnancy should be treated with the lowest possible dose of anithyroid drugs needed to keep the mother s thyroid hormone levels slightly above the normal range for total T4 and T3 values in pregnancy and the TSH suppressed. FreeT4 estimates should be kept at or slightly above the ULN of the nonpregnant normal range. Assess monthly and adjust dose as required
Management of hyperthyroidism in pregnancy R73: When thyroidectomy is necessary for the treatment of hyperthyroidism during pregnancy, the surgery should be performed if possible during the second trimester
The role of TRAb levels measurement in pregnancy R74: TRAb levels should be measured when the etiology of hyperthyroidism in pregnancy is uncertain R75: Patients who were treated with radioactive iodine or thyroidectomy for GD prior to pregnancy should have TRAb levels measured using a sensitive assay either initially at 22-26 weeks of gestation, or initially during the first trimester and, if elevated, again at 22-26 weeks
The role of TRAb levels measurement in pregnancy R76: Patients found to have GD during pregnancy should have TRAb levels measured at diagnosis using a sensitive assay and, if elevated, again at 22-26 weeks of gestation R77: TRAb levels measured at 22-26 weeks of gestation should be used to guide decisions regarding neonatal monitoring
Postpartum thyroiditis R78: In women with thyrotoxicosis after delivery, selective diagnostic studies performed to distinguish postpartum thyroiditis from GD Goiter generally more pronounced in GD Graves ophthalmopathy suggests GD Higher titers of TRAb and higher Total T4 to T3 ratio (>20) suggests GD If scan needed, 123-I or technetium preferred in breastfeeding over 131-I (discard breastmilk)
Postpartum thyroiditis Postpartum thyroid dysfunction occurs in up to 10% of pregnancies in the United States It is an autoimmune disorder unmasked in predisposed women as immune surveillance rebounds after pregnancy Classic triphasic pattern is thyrotoxicosis at 1-6 months postpartum, followed by hypothyroidism and return to euthyroidism at 9-12 months pp
Postpartum thyroiditis R79: In women with symptomatic postpartum thyrotoxicosis, the judicious use of betaadrenergic blocking agents is recommended. (beta-blockers secreted into breast milk at very low levels) Levothyroxine may be beneficial, at least transiently, for women with symptomatic hypothyroidism or having TSH levels > 10 mu/l
Painless thyroiditis An autoimmune disease manifested by positive ant-tpo antibodies and a triphasic pattern is some cases The postpartum period is the most common time when painless thyroiditis is seen Can also occur in nonpregnant females and men Can be associated with lithium or cytokine therapy
Subacute thyroiditis R96: Patients with mild symptomatic subacute thyroiditis should be treated with beta-blockers and non-steroidal anti-inflammatory agents. Those failing to respond or those with moderate-to-severe symptoms should be treated with corticosteroids
Drug-associated thyrotoxicosis Iodine-induced hyperthyroidism R88: Beta-adrenergic blocking agents alone or in combination with methimazole should be used to treat overt iodine-induced hyperthyroidism Cytokine-induced thyrotoxicosis R89: Patients who develop thyrotoxicosis during drug therapy with interferon-alpha or interleukin-2 should be evaluated to determine etiology (thyroiditis vs. GD) and treated accordingly
Drug-associated thyrotoxicosis Amiodarone-induced thyrotoxicosis R90: Monitor thyroid function tests before and at 1 and 3 months following initiation of amiodarone therapy, and at 3-6 month intervals thereafter R91: Test to distinguish type 1 (iodine-induced) from type 2 (thyroiditis) varieties of AIT R92: The decision to stop amiodarone in the setting of thyrotoxicosis should be determined on an individual basis and in consultation with Cardiology
Drug-associated thyrotoxicosis Amiodarone-induced thyrotoxicosis (cont.) R93: methimazole should be used to treat type 1 AIT and corticosteroids should be used to treat type 2 AIT. R94: Combined anithyroid drug and antiinflammatory therapy should be used to treat patients with overt AIT who fail to respond to single modality therapy, and in patients in whom the type of disease cannot be unequivocally determined R95: if unresponsive to medical therapy, surgery
Summary: Hypothyroidism and Hyperthyroidism We ve reviewed the essentials of diagnosing and treating hypothyroidism in the primary care setting and discussed conditions of special significance in hypothyroidism, such as pregnancy We ve reviewed the essentials of diagnosing and treating hyperthyroidism in the primary care setting and discussed the approach to treating special circumstances in hyperthyroidism, such as pregnancy, and the approach to treating drug-associated thyrotoxicosis.