Update In Hypothyroidism CME Away India & Sri Lanka March 23 - April 7, 2018 Richard A. Bebb MD, ABIM, FRCPC Consultant Endocrinologist Medical Subspecialty Institute Cleveland Clinic Abu Dhabi
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Barriers To Change
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Learning Objectives: Diagnosis of hypothyroidism Treatment of hypothyroidism T3/T4 Therapy Hypothyroidism in pregnancy Hypothyroidsm in the elderly
Fatigue Forgetfulness/Slower Thinking Nervousness/Irritability Depression Poor Mental Concentration and Memory Thinning Hair/Hair Loss Anemia Dry, Patchy Skin (Pilaris) Brittle Nails Cold Intolerance Elevated Cholesterol and Other Hyperlipidemias Effusion Personal History Endocrine/Autoimmune Disorders Eyelid Edema/Puffy Eyes Swelling (Goiter) Thyroiditis Hoarseness/Deepening of Voice Throat Pain Dysphagia Diastolic Hypertension Bradycardia Weight Gain Constipation Muscle Weakness/Cramps Infertility Menstrual Irregularities, Menometrorrhagia Tunbridge WM, et al. Clin Endocrinol (Oxf). 1977;7:481-493. Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68 Canaris GJ, et al Arch Intern Med. 2000;160:526-534. Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.
Case 1: 63 yr female 6 month history of fatigue, cold intolerance, unexplained weight gain, constipation Maternal family history of hypothyroidism Thyroid twice normal, symmetrical, indurated. Delayed reflexes TSH 8.4 (N 0.38-5.0 miu/l) {ug/ml} Free T4 12 (N 10.5-20 pmol/l) {0.8 ng/dl} Anti-thyroperoxidase 850 (N 0-35 IU/L)
Case 1: Rx 112 ug levothyroxine / day (1.6 ug/kg) 7 weeks later: feeling better constipation gone normal temperature perception still fatigued TSH 4.6
Case 1: Your advise? 1) she is euthyroid, Rx renewed 2) she needs triiodothyronine (T3) 3) she needs dessicated thyroid 4) she needs a T4 dose increase
Case 1: Follow-up The dose was increased to 125 ug / day 7 weeks later, she now feels normal. TSH 1.4 Therapeutic Targets in hypothyroidism: 1) a normal range TSH AND 2) a patient that feels normal
TSH distribution for a selected normal population (males 895, females 966, n=1,861) Hamilton, T. E. et al. J Clin Endocrinol Metab 2008;93:1224-1230
TSH Population Reference Range 95% Limits 0.3-0.4 1.3-1.4 2.5-3.0 ~ 4-5 10 TSH miu/l
Classical Causes of Primary Hypothyroidism Autoimmune Thyroid Disease (Hashimoto s Thyroiditis) Inflammatory Thyroiditis Subacute Silent Post Partum Surgery Radiation (I 131 & external beam) Drugs (lithium, amiodarone, interferon) Congenital Iodine deficiency
More recently recognized, and rare Etiologies of hypothyroidism 1) Chemotherapeutic Agents Ipilimumab, Bexarotene, Sunitinib (tyrosine kinase inhibitors) 2) Consumptive hypothyroidism (Type 3 deiodinase overexpression degrades T3 & T4 - paraneoplastic) Front Endocrinol (Lausanne). 2013; 4: 115)
Prevalence of Hypothyroidism Untreated Mild Thyroid Failure (MTF) 8.0% Untreated overt hypothyroidism 0.4% Treated hypothyroidism, TSH high 1.1% Treated hypothyroidism, TSH normal 3.5% Treated hypothyroidism, TSH low 1.3% Canaris GJ, et al. The Colorado thyroid disease prevalence study. Arch Intern Med 2000 Feb 28;160(4):526-34
Progression of Auto-immune Thyroid Disease Genetic predisposition Anti-TPO detected Mild Thyroid Failure Overt Hypothyroidism Environmental Triggers Years to decades 5-10% per year
Progression of Thyroid Failure Euthyroid Mild Thyroid Failure Overt Hypothyroidism TSH NORMAL RANGE T 4 T 3 Years Adapted from: Ayala AR, Wartofsky L. The Endocrinologist. 1997;7:44-50.
Case 2: 72 male with dyslipidemia Primary prevention Statin du jour 10 mg per day 3 weeks later complains of muscle cramps muscles and weakness CK elevated to 730 U/L ( normal < 171 U/L) 1 month later his muscle are better but not normal & C/O of insomnia and constipation
Case 2: TSH 18. Your Diagnosis? 1) Statin induced myopathy with sick euthyroid syndrome 2) Statin induced myopathy and statin induced thyroiditis 3) Previous hypothyroidism with associated dyslipidemia and associated myopathy 4) Primary dyslipidemia with statin intolerance due to hypothyroidism
Hypothyroidism and Dyslipidemia
Colorado Thyroid Disease Prevalence Study (N=25,862) % Abnormal Total CHOL, LDL-C, HDL-C Cholesterol LDL-C HDL-C % 70 60 50 40 30 20 10 0 70 60 50 40 30 20 10 0 70 60 50 40 30 20 10 0 Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.
Case 3: 36 female, prenatal visit 6 months of fatigue, heavier periods, 7 weeks of amenorrhea, dry skin Thyroid normal on exam but delayed DTR TSH 13.6, normal CBC, + pregnancy test Repeat TSH 12.5 (N 0.38-5.0 miu/l) {u/ml} Free T4 7 (N 10.5-20 pmol/l) {0.4 ng/dl}, anti-tpo negative (N 0-35 IU/L) Rx 125 ug levothyroxine per day (1.6 ug/kg)
Case 3: 5 weeks later (12 weeks GA) TSH 3.5. Rx unchanged 6 weeks later (18 weeks GA) TSH 9.6. Rx Levothyroxine 175 ug/day 6 weeks later (24 weeks GA) TSH 1.2.
Hypothyroidism in Pregnancy
Hypothyroidism: Maternal and Fetal Risks Maternal Miscarriages Pregnancy-Induced Hypertension (PIH) Preterm delivery Postpartum hemorrhage Fetal Small for Gestational Age (SGA) Intrauterine Growth Restriction (IUGR) Prematurity Rare transient congenital hypothyroidism Loss of IQ
Hypothyroidism in Pregnancy & IQ of children Fetal neuropsychological development Cognitive testing of children age 7-9 Untreated hypothyroid mothers vs. normal mothers: Average of 7 IQ points less in children Increased risk of IQ < 85 (19% vs. 5%) Retrospective study NEJM 1999; 341: 549-55.
Hypothyroidism in Pregnancy & IQ of children However. Lazarus et al. Antenatal Thyroid Screening and Childhood Cognitive Function (n=390 +, 404 -, 21,846 screened) No change in cognitive function at 3 yrs. Casey et al. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy No change in cognitive outcome at 5 yrs. NEJM 2012; 366:493-501 NEJM 2017; 376(9): 376-9
Clinical Guidelines for Treating Hypothyroidism Before and During Pregnancy In hypothyroid women planning a pregnancy LT4 dose adjusted to achieve a TSH less than 2.5 mu/l. Increase the L-thyroxine dosage in athyreotic patients by 20 to 30% when pregnancy is confirmed (50 to 85% will require an increase) Monitor TSH every 4 wks. Reinstate pre-pregnancy L-thyroxine dosage immediately following delivery (Recheck TSH in 6 weeks) THYROID Volume 27, (3), 2017 American Thyroid Association
2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum TSH over 10 regardless of anti-tpo status: Treat with T4 (Strong Recommendation) TSH of 4 to 9.9 AND positive anti-tpo antibodies: Treat with T4 (Strong Recommendation) TSH of 4 to 9.9 and negative anti-tpo : Consider treatment with T4 (Weak recommendation) TSH between 2.5 and 4.0 AND anti-tpo positive: Consider Treatment with T4 (Weak recommendation) Particularly if prior SA. TSH less than 4 and NO anti-tpo antibodies: Do NOT treat TSH less than 2.5 BUT anti-tpo antibodies: Do not treat with T4 BUT check TSH every 4 weeks THYROID Volume 27, (3), 2017 American Thyroid Association
Mild Thyroid Failure: What to do?
Case 4-62 year old woman with subclinical hypothyroidism. TSH 7.24, free T4 14.3 pmol/l (1.11 ng/dl) Repeat 3 months later TSH 3.58 Repeat 2 months later TSH 4.08 Followed without treatment. Over the next 18 months TSH 3.7 4.6 range. She is still tired.
Treatment Controversies: People with TSH 4.5-9.9 mu/l Observational data Do not suggest harm in following with TSH <7 miu/l Increased CV risk for untreated TSH 7 miu/l RCT data No harm or benefit in treating older patients No hard outcomes in available RCTs
SUBCLINICAL HYPOTHYROIDISM METANALYSES CHD and Mortality Ten studies evaluating Subclinical Hypothyroidism CHD RR 1.2 Higher quality studies: LOWER: RR (1.02-1.08) Older than 65 : LOWER: RR (0.98-1.26) Younger than 65 : HIGHER: RR (1.09.-2.09) Conclusion: Untreated hypothyroidism may increase risk of CHD, particularly in younger than 65 Ochs, AIM, 2008
Subclinical Hypothyroidism: Management Patients who have symptoms Following TSH levels or a therapeutic trial of low dose LT4 are both reasonable. Asymptomatic Follow, treat TSH 7 miu/l Over the age of 65 Follow, treat TSH 7 miu/l If treat, less aggressive goal TSH
When to treat Mild Thyroid Failure TSH elevated Normal free T4 (reproducibly) TSH > 10 TSH 5-10 Treat Pregnancy or infertility Goiter Diabetes or dyslipidemia High anti-tpo Titer Not pregnant Normal Thyroid Size No DM or dyslipidemia Low anti-tpo Titer Treat Observe retest TSH every 6 months
Subclinical Hypothyroidism Impact on Ischemic Heart Disease Events Age (years) BIONDI, COOPER ENDOCR REV 2008
The normal curve widens & shifts to the right in the Elderly Age 20-29 Age 50-59 Age 80+ Surks M, Hollowell J. JCEM 2007;92:4575-82
Summary of findings TRUST Trial RCT of levothyroxine versus placebo 737 men and women aged 65 years and older with persistent subclinical hypothyroidism, not selected based on symptoms Mean baseline TSH 6.4 miu/l Levothyroxine (median dose 50 µg) reduced TSH by approximately 2 miu/ L Stott D et al, NEJM. 2017;376(26):2534-2544.
Summary of findings TRUST Trial RCT of levothyroxine versus placebo No effect of LT4 on Hypothyroid symptoms or Fatigue scores at 12m No effect on handgrip strength, digit symbol substitution, BP, weight, BMI, waist circumference No evidence of effect on cardiovascular events No excess of adverse events of special interest, no increase in Hyperthyroid symptoms Stott D et al, NEJM. 2017;376(26):2534-2544.
Summary of findings TRUST Trial RCT of levothyroxine versus placebo Limitations Few participants with baseline TSH >10 Symptom levels low; cannot exclude possible benefit in persons with more marked complaints Stott D et al, NEJM. 2017;376(26):2534-2544.
Thyroid Hormone Replacement
Treatment Algorithm Levothyroxine sodium is the treatment of choice Adults 1.6 mcg/kg of body weight/day Elderly and CV patients <1.0 mcg/kg/day Clinical and biochemical evaluations at 4 to 6 week intervals until the serum TSH concentration is normalized. It is preferable to maintain the patient on the same brand throughout treatment.
% Participants Thyroid Status Among Treated Participants (n=1525) 100 80 Oversuppressed >20% Undertreated >18% 60 60.1% 40 20 20.7% 17.6% 0 0.9% 0.7% Hyperthyroid Subclinical Euthyroid Subclinical Hypothyroid Hyperthyroid Hypothyroid Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.
Data derived from Mayor et al. 1995, Dong et al. 1997
Thyroid Extract (aka Dried Animal Thyroid) T4:T3 ratio 4.2:1 T4:T3 ratio in rats 4:1 T4:T3 ratio in humans 14:1
Thyroid Extract or T3/T4 Combination Therapy Probable Harm to Fetus Fetal type 2 deiodinase converts maternal T4 to T3, the primary source of thyroid hormone through week 16 of gestation Maternal T3 does not appear effectively cross placenta Thus maternal hypothyroxinemia seen in mothers taking extract may have adverse effects on fetal development
Cytomel (T3) Rarely used by itself unless dye allergies or T4 resistance Start with 5-10 micrograms/day if used with T4 Usual maintenance dose is 25-75 micrograms/day if used alone
Polymorphisms in the Type 2 Deiodinase D2 Thr92Ala polymorphism The dose of levothyroxine required to suppress TSH to 0.1 Ala/Ala 2.08 + 0.43 mcg/kg P<0.05 Thr/Ala 1.89 + 0.32 Thr/Thr 1.92 + 0.39 Torlontano et al JCEM 2008
Polymorphisms in the Type 2 deiodinase Pre-op versus Post-thyroidectomy T3 Lower T3 despite identical TSH levels TSH 0.93 + 0.6 versus TSH 0.91 + 0.6 Cartagna et al JCEM 2017
ATA Guidelines For patients with primary hypothyroidism who feel unwell on levothyroxine therapy, there is currently insufficient evidence to support the routine use of a trial of combination therapy
ETA Guidelines It is suggested that L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated patients who have persistent complaints
Suggested Candidates for a Trial of Combined Therapy YES Patients who have never felt well after a thyroidectomy or after ablative therapy with radioiodine NO Pregnant or planning a pregnancy Elderly or patients with cardiovascular disease Patients who previously felt well on L-T4?
Do Not Over treat
0.00 0.20 0.40 0.60 0.80 1.00 Atrial Fibrillation CARDIOVASCULAR HEALTH STUDY Incident atrial fibrillation by thyroid group TSH < 0.1 TSH 0.1-0.4 euthyroid subclinical hypothyroid overt hypothyroid 0 2 4 6 8 10 12 Years Incidence (per 1000 person-years) 126 (p=0.001) 59 (p=0.007) 31 Cappola et al, JAMA. 2006;295:1033-41
Subclinical Hyperthyroidism and Fracture Risk Blum M et al, JAMA. 2015;313(20):2055-2065.