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Hypothyroidism Katherine Stanley, MD January 14, 2008.

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1 Hypothyroidism Katherine Stanley, MD January 14, 2008

2 Definitions Overt hypothyroidism: serum TSH above upper limit of normal, free T4 below lower limit Overt hypothyroidism: serum TSH above upper limit of normal, free T4 below lower limit Subclinical hypothyroidism- serum TSH above upper limit, free T4 in normal range Subclinical hypothyroidism- serum TSH above upper limit, free T4 in normal range

3 Epidemiology 1 Subclinical 5% of adults Subclinical 5% of adults Overt 0.1-2% of adults Overt 0.1-2% of adults 2% of adolescents (subclinical and overt) 2% of adolescents (subclinical and overt) 5-8x more common in women 5-8x more common in women Congenital HT in 1:4000 newborns Congenital HT in 1:4000 newborns

4 Clinical Manifestations Constitutional Constitutional –Fatigue, weight gain, cold intolerance Skin Skin –Coarse hair and skin, brittle nails, puffy facies, nonpitting edema HEENT HEENT –Enlargement of tongue, periorbital edema, hoarseness

5 Clinical Manifestations Cardiovascular Cardiovascular –Bradycardia, decreased contractility, increased SVR->incr diastolic BP, increased cholesterol (2x the general population) 2, increased homocysteine, pericardial effusions Respiratory Respiratory –DOE, rhinitis, decreased exercise capacity, OSA (macroglossia), pleural effusions

6 Clinical Manifestations GI GI –Constipation Heme Heme –Normocytic anemia, macrocytic anemia (pernicious), hypocoagulable state, incr LDH Renal Renal –Hyponatremia, increased creatinine

7 Clinical Manifestations Reproductive Reproductive –Menstrual irregularities, decreased fertility, incr prolactin, decr libido, ED, delayed ejaculation Musculoskeletal Musculoskeletal –Delayed DTRs, myalgias, arthralgias, incr CK, carpal tunnel Neurologic Neurologic –Depression, dementia, Hashimoto’s encephalopathy, myxedema coma

8 A few words about myxedema coma Presents w/ altered consciousness, hypothermia, hypoglycemia, hyponatremia, hypoventilation, bradycardia, hypotension Presents w/ altered consciousness, hypothermia, hypoglycemia, hyponatremia, hypoventilation, bradycardia, hypotension Mortality 30-40% Mortality 30-40% Treatment Treatment –IV T4- load mcg, f/b mcg/day –Use of T3 controversial –Glucorticoids until adrenal insufficiency ruled out

9 Clinical Manifestations in Children Most common manifestation is declining growth velocity, short stature Most common manifestation is declining growth velocity, short stature –Generally insidious –May be only symptom Altered school performance Altered school performance –May actually improve in some children Delayed pubertal development Delayed pubertal development Enlarged sell turcica 2/2 hyperplasia of thyrotroph cells Enlarged sell turcica 2/2 hyperplasia of thyrotroph cells –Rarely symptomatic –Reversible with therapy

10 Other reasons to check the TSH Goiter Goiter Surgery around the thyroid Surgery around the thyroid Irradiation Irradiation Drugs that affect thyroid Drugs that affect thyroid –Lithium, amiodarone Autoimmune diseases Autoimmune diseases –DM 1, pernicious anemia, vitiligo, primary adrenal insufficiency, PBC Chromosomal disorders, eg Down’s, Turner’s, Klinefelter’s Chromosomal disorders, eg Down’s, Turner’s, Klinefelter’s

11 Causes of Hypothyroidism Chronic autoimmune thyroiditis (Hashimoto’s) Chronic autoimmune thyroiditis (Hashimoto’s) –Most common cause in both children and adults Thyroidectomy Thyroidectomy –2-4 weeks with total, variable with subtotal Neck irradiation Neck irradiation Radioiodine therapy Radioiodine therapy Iodine- deficiency or excess Iodine- deficiency or excess Drugs Drugs –Lithium, amiodarone, kelp, IFN-a, IL-2, contrast Infiltrative disease Infiltrative disease

12 Hypothyroidism in Childhood Cancer Survivors One study found that 36% of childhood cancer survivors had developed primary HT, 32% central/mixed 3 One study found that 36% of childhood cancer survivors had developed primary HT, 32% central/mixed 3 Major risk is from radiation to head and neck Major risk is from radiation to head and neck –Current guidelines recommend yearly TSH and T4 in such patients 4 May be some risk from chemo alone May be some risk from chemo alone –30% of the patients in above study had not received any radiation

13 Diagnosis Check the TSH Check the TSH –98% sensitive, 92% specific Why is TSH the best test? Why is TSH the best test? –T4 has wide range of normal –Everyone has endogenous optimum set point –TSH will increase when fall below set point If TSH increased, check free T4 If TSH increased, check free T4

14 Tricky Thyroid- when TSH doesn’t work Secondary/Tertiary Hypothyroidism Secondary/Tertiary Hypothyroidism –TSH can be low, inappropriately nl, or slightly high (biologically inactive) –Check FT4 if suspect –Suspect if: known hypothalamic or pituitary dz, prior cranial irradiation, mass lesion in pituitary, s/sx of other hormonal deficiencies Drugs that affect Thyroid Testing Drugs that affect Thyroid Testing –See next slide Don’t forget about sick euthyroid Don’t forget about sick euthyroid

15 Drugs and Thyroid Testing Decreased TSH secretion Decreased TSH secretion –Glucocorticoids, dopamine Decreased TBG Decreased TBG –Glucocorticoids, androgens, niacin Increased TBG Increased TBG –Estrogens, tamoxifen, methadone, heroin, clofibrate Increased T4 clearance Increased T4 clearance –Phenytoin, carbamazepine, rifampin, phenobarbital Decreased T4 binding to TBG Decreased T4 binding to TBG –Furosemide, heparin, salicylates, NSAIDs

16 To screen or not to screen? American Thyroid Association recommends universal screening q5yrs beginning at 35 5 American Thyroid Association recommends universal screening q5yrs beginning at 35 5 –High prevalence –Known clinical consequences –Accurate, available, safe, inexpensive assay –Effective treatment Cost effectiveness analysis published in JAMA 6 found $9223 per quality adjusted life year (QALY) in women, $22595 per QALY in men, mostly based on relieving sxs associated with thyroid failure Cost effectiveness analysis published in JAMA 6 found $9223 per quality adjusted life year (QALY) in women, $22595 per QALY in men, mostly based on relieving sxs associated with thyroid failure

17 To screen or not to screen? U.S. Preventive Task Force Guidelines declares evidence insufficient to recommend routine screening 7 U.S. Preventive Task Force Guidelines declares evidence insufficient to recommend routine screening 7 –Poor evidence that treatment improves clinically important outcomes –Low PPV in primary care population

18 Treatment Average required dose is 1.6 mcg/kg Average required dose is 1.6 mcg/kg Required dose more closely w/lean body mass than fat mass 8 Required dose more closely w/lean body mass than fat mass 8 –May want to consider dosing closer to ideal body weight in obese pts

19 Treatment in children Children clear T4 more rapidly than adults Children clear T4 more rapidly than adults –Age 1-3: 4-6 mcg/kg –Age 3-10: 3-5 mcg/kg –Age mcg/kg Avoid overtreatment Avoid overtreatment –Maintain TSH in lower nl range, T4 in upper normal –Can cause craniosynostosis in infants, deleterious effects on behavior, school performance, growth May spontaneously remit, but should continue treatment until complete growth and puberty May spontaneously remit, but should continue treatment until complete growth and puberty

20 Start low, go slow? Some physicians adhere to this principal in all pts Some physicians adhere to this principal in all pts RCT comparing full dose vs. low starting dose of 25 mcg 9 RCT comparing full dose vs. low starting dose of 25 mcg 9 –Excluded pts with known cardiac disease –Everyone remaining screened with dobutamine stress echos –Full dose group reached euthyroidism more quickly –No cardiac events in either group –No difference in rate of QOL improvement or cholesterol improvement

21 So… Pts older than 65, known cardiac disease should start at 25 mcg Pts older than 65, known cardiac disease should start at 25 mcg Young, healthy patients should start at full dose (1.6 mcg/kg) Young, healthy patients should start at full dose (1.6 mcg/kg) Check TSH 3-6 wks after starting and after any changes Check TSH 3-6 wks after starting and after any changes

22 What brand should I use? Bioequivalence studies of Synthroid, Levoxyl, and 2 generic preps showed no significant differences for area under curve, time to peak, peak conc of T3, T4, and FTI 10 Bioequivalence studies of Synthroid, Levoxyl, and 2 generic preps showed no significant differences for area under curve, time to peak, peak conc of T3, T4, and FTI 10 However, FDA recommends remaining on same preparation, checking TSH after 6 wks if pt must change 11 However, FDA recommends remaining on same preparation, checking TSH after 6 wks if pt must change 11

23 What if my patient won’t take their Synthroid? T4 has very long half life T4 has very long half life Can give total weekly dose qwk 12 Can give total weekly dose qwk 12 Caveat- above recommendation based on small, relatively short study Caveat- above recommendation based on small, relatively short study

24 What if my pt wants more Synthroid? Pts often say they feel better on higher doses which put their TSH in lower range of normal, even a bit hyperthyroid Pts often say they feel better on higher doses which put their TSH in lower range of normal, even a bit hyperthyroid Double blind crossover study comparing low, middle, and high doses 113 Double blind crossover study comparing low, middle, and high doses 113 –No difference in quality of life, cognitive measurements when compared both based on dose and TSH level

25 Special Cases- Cardiac Disease 14 Treatment should improve cholesterol, DBP, contractility Treatment should improve cholesterol, DBP, contractility Improves angina in some (38%), 46% have no change, 16% have increased sxs Improves angina in some (38%), 46% have no change, 16% have increased sxs No evidence of decr CV M&M with tx of hypothyroidism No evidence of decr CV M&M with tx of hypothyroidism Some evidence of increased CV M&M when initiating treatment Some evidence of increased CV M&M when initiating treatment Generally, start very slowly (25 mcg), consider extensive cardiac assessment, eg stress or angio, and possible medical tx and/or stenting or CABG Generally, start very slowly (25 mcg), consider extensive cardiac assessment, eg stress or angio, and possible medical tx and/or stenting or CABG

26 Special Cases-Elderly Another population to start slowly with, perhaps consider not treating Another population to start slowly with, perhaps consider not treating Cohort study addressing disability and survival in old age in relation to thyroid status 15 Cohort study addressing disability and survival in old age in relation to thyroid status 15 –No difference in mortality rate, decline in cognitive fxn, decline in ability to carry out ADLs and IADLs, depression with increased TSH –May even have decr mortality w/incr TSH ?Survival benefit ?Survival benefit

27 Special Cases- Subclinical 16 TSH , no treatment TSH , no treatment –Rate of progression 2.6% Ab-, 4.3% Ab+ –Monitor TSH q6-12 mos TSH >10, consider tx given 5% rate of progression to overt but inconclusive evidence of benefit TSH >10, consider tx given 5% rate of progression to overt but inconclusive evidence of benefit Pregnancy, treat given evidence of worsened fetal outcomes Pregnancy, treat given evidence of worsened fetal outcomes Treated overt, adjust dosage Treated overt, adjust dosage

28 What if I have SHT and …? Depression 17,19 Depression 17,19 –No difference in cognitive and emotional fxn between those with SHT (TSH ) and without –No difference in above in those with SHT after tx w/T4 vs. placebo Obesity 18,19 Obesity 18,19 –No diff in BMI or body weight after tx of SHT High cholesterol 20,2 High cholesterol 20,2 –While pts w/SHT may have worse lipid profiles, no beneficial effect of tx has been conclusively shown Fatigue 19 Fatigue 19 –No difference in impr btw treatment and placebo

29 Subclinical hypothyroidism in children 21 Baseline TSH less predictive of rate of progression than in adults Baseline TSH less predictive of rate of progression than in adults Higher baseline thyroglobulin Ab and thyroid volume may be predictive Higher baseline thyroglobulin Ab and thyroid volume may be predictive Increasing TPO Ab over time may be indicative of declining thyroid fxn Increasing TPO Ab over time may be indicative of declining thyroid fxn No growth retardation in children w/SHT followed over 5 years No growth retardation in children w/SHT followed over 5 years Treatment is controversial 22,23 Treatment is controversial 22,23

30 Special Cases-Pregnancy Increased TBG, T4 clearance, and transfer of T4 to fetus Increased TBG, T4 clearance, and transfer of T4 to fetus Increased requirement 8 wks, wk 16 Increased requirement 8 wks, wk 16 Consider increasing dose when pregnancy confirmed, then check TSH q4wks until TSH nl Consider increasing dose when pregnancy confirmed, then check TSH q4wks until TSH nl

31 Special Cases-Congenital hypothyroidism Most common treatable cause of mental retardation Most common treatable cause of mental retardation Etiologies Etiologies –Most common is thyroid dysgenesis –Defects in thyroid hormone synthesis, secretion, and transport –Central- congenital syndromes, birth injury, insufficient tx of maternal hyperthyroidism –Transient-iodine deficiency or exposure, antithyroid drugs, maternal transfer of blocking antibodies

32 Congenital HT 24 Clinical Manifestations Clinical Manifestations –Lethargy, slow movement, hoarse cry, feeding difficulties, constipation, macroglossia, umbilical hernia, large fontanels, hypotonia, dry skin, hypothermia, prolonged jaundice But most infants have few if any s/sx But most infants have few if any s/sx Hence part of newborn screen Hence part of newborn screen –Some screens check T4, some check TSH –Advantages and disadvantages of both Treatment Treatment –Oral T4 (crushed pills) –10-15 mcg/day –Avoid soy formula

33 Congenital HT Prognosis Prognosis –Normal growth, development, and intelligence if treated early (<2 wks) –Improved outcomes with higher initial T4 dose and shortened time to target T4 and TSH 25

34 Special Cases-Drugs affecting Treatment Drugs that affect TBG or binding of T4 to TBG Drugs that affect TBG or binding of T4 to TBG –I already told you Drugs that decrease absorption of T4 Drugs that decrease absorption of T4 –Cholestyramine, CaCO3, FeSO4, sucralfate, PPIs, and others

35 Special Cases- Surgery Higher incidence of ileus, hypotension, hyponatremia, CNS dysfunction Higher incidence of ileus, hypotension, hyponatremia, CNS dysfunction Consider postponing elective surgeries Consider postponing elective surgeries Not urgent surgeries, just be aware of slightly increased complications Not urgent surgeries, just be aware of slightly increased complications

36 References 1 Hollowell, JG et al. Serum TSH, T4, and thyroid antibodies in the US population ( ): National Health and Nutrition Examination Survey (NHANES III). JCEM 2002: Diekman, T et al. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med 1995; 155: Rose, SB et al. Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. JCEM 1999: Children’s Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. National Guidelines Clearinghouse 2006: 5 Ladenson, P et al. American Thyroid Association Guidelines for Detection of Thyroid Dysfunction. Arch Intern Med 2000; 160: Danesee, MD et al. Screening for mild thyroid failure at the periodic health examination: a decision and cost-effectiveness analysis. JAMA 1996; 276: US Preventive Services Task Force. Screening for thyroid disease: recommendation statement. National Guidelines Clearinghouse 2004: 8 Santini, F et al. Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid diseases. JCEM 2005; 90-: Roos, A et al. The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med 2005; 165: Dong, BJ et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997: 277: Joint statement on the U.S Food and Drug Administration’s decision regarding bioequivalence of levothyroxine sodium. Thyroid 2004; 14: Grebe, SKG et al. Treatment of hypothyroidism with once weekly thyroxine. JCEM 1997; 82: Walsh, JP et al. Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life: results of a double-blind, randomized clinical trial

37 References 14 Feldt-Rasmussen, U. Treatment of hypothyroidism in elderly patients and in patients with cardiac disease. Thyroid 2007; 16: Feldt-Rasmussen, U. Treatment of hypothyroidism in elderly patients and in patients with cardiac disease. Thyroid 2007; 16: Gussekloo J. Thyroid Status, disability and cognitive function, and survival in old age. JAMA 2004; 292: Gussekloo J. Thyroid Status, disability and cognitive function, and survival in old age. JAMA 2004; 292: Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. National Guidelines Clearinghouse Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. National Guidelines Clearinghouse Jorde, et al. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. JCEM 2006; 91: Jorde, et al. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. JCEM 2006; 91: Portmann L. Obesity and hypothyroidism: myth or reality? Revue Medicale Suisse 2007; 105: Portmann L. Obesity and hypothyroidism: myth or reality? Revue Medicale Suisse 2007; 105: Kong, WK, et al. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med. 2002; 112: Kong, WK, et al. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med. 2002; 112: Pearce, EN. Hypothyroidism and dyslipidemia: modern concepts and approaches. Current Cardiology Reports 2004; 6: Pearce, EN. Hypothyroidism and dyslipidemia: modern concepts and approaches. Current Cardiology Reports 2004; 6: Radetti G. et al. The natural history of euthyroid Hashimoto’s thyroiditis in children. J Pediatr. 2006; 149: Radetti G. et al. The natural history of euthyroid Hashimoto’s thyroiditis in children. J Pediatr. 2006; 149: Fatourechi, Vahab. Subclinical hypothryoidism: how should it be managed? Treatments in Endocrinology 2002; 1: Fatourechi, Vahab. Subclinical hypothryoidism: how should it be managed? Treatments in Endocrinology 2002; 1: Moore, DC. Natural course of ‘subclinical’ hypothyroidism in childhood and adolescence. Arch Pediatr Adolesc Med 1996; 150: Moore, DC. Natural course of ‘subclinical’ hypothyroidism in childhood and adolescence. Arch Pediatr Adolesc Med 1996; 150: Rose, SR et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006; 117: Rose, SR et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006; 117:2290.

38 References 25 Selva, KA et al. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. J Pediatr 2005; 147: Selva, KA et al. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. J Pediatr 2005; 147: Surks, M. Clinical manifestations of hypothyroidism. 26 Surks, M. Clinical manifestations of hypothyroidism. 27 Ross, DS. Diagnosis of and screening for hypothyroidism. 27 Ross, DS. Diagnosis of and screening for hypothyroidism. 28 Ross, DS. Treatment of hypothyroidism. 28 Ross, DS. Treatment of hypothyroidism. 29 Green, GB. Hypothyroidism. Washington Manual of Medical Therapeutics. Lippincott Williams & Wilkins, Philadelphia, 2004: Green, GB. Hypothyroidism. Washington Manual of Medical Therapeutics. Lippincott Williams & Wilkins, Philadelphia, 2004: Ross, DS. Myxedema coma. 30 Ross, DS. Myxedema coma. 31 LaFranchi, S. Acquired hypothyroidism in childhood and adolescence. 31 LaFranchi, S. Acquired hypothyroidism in childhood and adolescence. 32 LaFranchi, S. Clnical features and detection of congenital hypothyroidism. 32 LaFranchi, S. Clnical features and detection of congenital hypothyroidism. 33 LaFranchi, S. Treatment and prognosis of congenital hypothyroidism. 33 LaFranchi, S. Treatment and prognosis of congenital hypothyroidism.

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