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Hypothyroidism. Katherine Stanley, MD January 14, 2008. Definitions. 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. Epidemiology 1. Subclinical 5% of adults

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Hypothyroidism l.jpg

Hypothyroidism

Katherine Stanley, MD

January 14, 2008


Definitions l.jpg
Definitions

  • 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


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Epidemiology1

  • Subclinical 5% of adults

  • Overt 0.1-2% of adults

  • 2% of adolescents (subclinical and overt)

  • 5-8x more common in women

  • Congenital HT in 1:4000 newborns


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Clinical Manifestations

  • Constitutional

    • Fatigue, weight gain, cold intolerance

  • Skin

    • Coarse hair and skin, brittle nails, puffy facies, nonpitting edema

  • HEENT

    • Enlargement of tongue, periorbital edema, hoarseness


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Clinical Manifestations

  • Cardiovascular

    • Bradycardia, decreased contractility, increased SVR->incr diastolic BP, increased cholesterol (2x the general population)2, increased homocysteine, pericardial effusions

  • Respiratory

    • DOE, rhinitis, decreased exercise capacity, OSA (macroglossia), pleural effusions


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Clinical Manifestations

  • GI

    • Constipation

  • Heme

    • Normocytic anemia, macrocytic anemia (pernicious), hypocoagulable state, incr LDH

  • Renal

    • Hyponatremia, increased creatinine


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Clinical Manifestations

  • Reproductive

    • Menstrual irregularities, decreased fertility, incr prolactin, decr libido, ED, delayed ejaculation

  • Musculoskeletal

    • Delayed DTRs, myalgias, arthralgias, incr CK, carpal tunnel

  • Neurologic

    • Depression, dementia, Hashimoto’s encephalopathy, myxedema coma


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A few words about myxedema coma

  • Presents w/ altered consciousness, hypothermia, hypoglycemia, hyponatremia, hypoventilation, bradycardia, hypotension

  • Mortality 30-40%

  • Treatment

    • IV T4- load 200-400 mcg, f/b 50-100 mcg/day

    • Use of T3 controversial

    • Glucorticoids until adrenal insufficiency ruled out


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Clinical Manifestations in Children

  • Most common manifestation is declining growth velocity, short stature

    • Generally insidious

    • May be only symptom

  • Altered school performance

    • May actually improve in some children

  • Delayed pubertal development

  • Enlarged sell turcica 2/2 hyperplasia of thyrotroph cells

    • Rarely symptomatic

    • Reversible with therapy


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Other reasons to check the TSH

  • Goiter

  • Surgery around the thyroid

  • Irradiation

  • Drugs that affect thyroid

    • Lithium, amiodarone

  • Autoimmune diseases

    • DM 1, pernicious anemia, vitiligo, primary adrenal insufficiency, PBC

  • Chromosomal disorders, eg Down’s, Turner’s, Klinefelter’s


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Causes of Hypothyroidism

  • Chronic autoimmune thyroiditis (Hashimoto’s)

    • Most common cause in both children and adults

  • Thyroidectomy

    • 2-4 weeks with total, variable with subtotal

  • Neck irradiation

  • Radioiodine therapy

  • Iodine- deficiency or excess

  • Drugs

    • Lithium, amiodarone, kelp, IFN-a, IL-2, contrast

  • Infiltrative disease


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Hypothyroidism in Childhood Cancer Survivors

  • One study found that 36% of childhood cancer survivors had developed primary HT, 32% central/mixed3

  • Major risk is from radiation to head and neck

    • Current guidelines recommend yearly TSH and T4 in such patients4

  • May be some risk from chemo alone

    • 30% of the patients in above study had not received any radiation


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Diagnosis

  • Check the TSH

    • 98% sensitive, 92% specific

  • 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


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Tricky Thyroid- when TSH doesn’t work

  • 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

    • See next slide

  • Don’t forget about sick euthyroid


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Drugs and Thyroid Testing

  • Decreased TSH secretion

    • Glucocorticoids, dopamine

  • Decreased TBG

    • Glucocorticoids, androgens, niacin

  • Increased TBG

    • Estrogens, tamoxifen, methadone, heroin, clofibrate

  • Increased T4 clearance

    • Phenytoin, carbamazepine, rifampin, phenobarbital

  • Decreased T4 binding to TBG

    • Furosemide, heparin, salicylates, NSAIDs


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To screen or not to screen?

  • American Thyroid Association recommends universal screening q5yrs beginning at 355

    • High prevalence

    • Known clinical consequences

    • Accurate, available, safe, inexpensive assay

    • Effective treatment

  • Cost effectiveness analysis published in JAMA6 found $9223 per quality adjusted life year (QALY) in women, $22595 per QALY in men, mostly based on relieving sxs associated with thyroid failure


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To screen or not to screen?

  • U.S. Preventive Task Force Guidelines declares evidence insufficient to recommend routine screening7

    • Poor evidence that treatment improves clinically important outcomes

    • Low PPV in primary care population


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Treatment

  • Average required dose is 1.6 mcg/kg

  • Required dose more closely w/lean body mass than fat mass8

    • May want to consider dosing closer to ideal body weight in obese pts


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Treatment in children

  • Children clear T4 more rapidly than adults

    • Age 1-3: 4-6 mcg/kg

    • Age 3-10: 3-5 mcg/kg

    • Age 10-16 2-4 mcg/kg

  • 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


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Start low, go slow?

  • Some physicians adhere to this principal in all pts

  • RCT comparing full dose vs. low starting dose of 25 mcg9

    • 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


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So…

  • Pts older than 65, known cardiac disease should start at 25 mcg

  • Young, healthy patients should start at full dose (1.6 mcg/kg)

  • Check TSH 3-6 wks after starting and after any changes


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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 FTI10

  • However, FDA recommends remaining on same preparation, checking TSH after 6 wks if pt must change11


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What if my patient won’t take their Synthroid?

  • T4 has very long half life

  • Can give total weekly dose qwk12

  • Caveat- above recommendation based on small, relatively short study


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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

  • Double blind crossover study comparing low, middle, and high doses113

    • No difference in quality of life, cognitive measurements when compared both based on dose and TSH level


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Special Cases- Cardiac Disease14

  • Treatment should improve cholesterol, DBP, contractility

  • Improves angina in some (38%), 46% have no change, 16% have increased sxs

  • No evidence of decr CV M&M with tx of hypothyroidism

  • 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


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Special Cases-Elderly

  • Another population to start slowly with, perhaps consider not treating

  • Cohort study addressing disability and survival in old age in relation to thyroid status15

    • 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


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Special Cases- Subclinical16

  • TSH 4.5-10, 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

  • Pregnancy, treat given evidence of worsened fetal outcomes

  • Treated overt, adjust dosage


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What if I have SHT and …?

  • Depression17,19

    • No difference in cognitive and emotional fxn between those with SHT (TSH 3.5-10) and without

    • No difference in above in those with SHT after tx w/T4 vs. placebo

  • Obesity18,19

    • No diff in BMI or body weight after tx of SHT

  • High cholesterol20,2

    • While pts w/SHT may have worse lipid profiles, no beneficial effect of tx has been conclusively shown

  • Fatigue19

    • No difference in impr btw treatment and placebo


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Subclinical hypothyroidism in children21

  • Baseline TSH less predictive of rate of progression than in adults

  • Higher baseline thyroglobulin Ab and thyroid volume may be predictive

  • Increasing TPO Ab over time may be indicative of declining thyroid fxn

  • No growth retardation in children w/SHT followed over 5 years

  • Treatment is controversial22,23


Special cases pregnancy l.jpg
Special Cases-Pregnancy

  • Increased TBG, T4 clearance, and transfer of T4 to fetus

  • Increased requirement begins @ 8 wks, plateaus @ wk 16

  • Consider increasing dose when pregnancy confirmed, then check TSH q4wks until TSH nl


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Special Cases-Congenital hypothyroidism

  • Most common treatable cause of mental retardation

  • 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


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Congenital HT24

  • 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

  • Hence part of newborn screen

    • Some screens check T4, some check TSH

    • Advantages and disadvantages of both

  • Treatment

    • Oral T4 (crushed pills)

    • 10-15 mcg/day

    • Avoid soy formula


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Congenital HT

  • 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 TSH25


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Special Cases-Drugs affecting Treatment

  • Drugs that affect TBG or binding of T4 to TBG

    • I already told you

  • Drugs that decrease absorption of T4

    • Cholestyramine, CaCO3, FeSO4, sucralfate, PPIs, and others


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Special Cases- Surgery

  • Higher incidence of ileus, hypotension, hyponatremia, CNS dysfunction

  • Consider postponing elective surgeries

  • Not urgent surgeries, just be aware of slightly increased complications


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References

1 Hollowell, JG et al. Serum TSH, T4, and thyroid antibodies in the US population (1988-1994): National Health and Nutrition Examination Survey (NHANES III). JCEM 2002: 489.

2 Diekman, T et al. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med 1995; 155: 1490.

3 Rose, SB et al. Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. JCEM 1999: 4472.

4 Children’s Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. National Guidelines Clearinghouse 2006: www.guideline.gov.

5 Ladenson, P et al. American Thyroid Association Guidelines for Detection of Thyroid Dysfunction. Arch Intern Med 2000; 160: 1573.

6 Danesee, MD et al. Screening for mild thyroid failure at the periodic health examination: a decision and cost-effectiveness analysis. JAMA 1996; 276: 285.

7 US Preventive Services Task Force. Screening for thyroid disease: recommendation statement. National Guidelines Clearinghouse 2004: www.guideline.gov.

8 Santini, F et al. Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid diseases. JCEM 2005; 90-: 124. 9 Roos, A et al. The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med 2005; 165: 1714.

10 Dong, BJ et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997: 277: 1205.

11 Joint statement on the U.S Food and Drug Administration’s decision regarding bioequivalence of levothyroxine sodium. Thyroid 2004; 14:486.

12 Grebe, SKG et al. Treatment of hypothyroidism with once weekly thyroxine. JCEM 1997; 82: 870.

13 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


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References

  • 14 Feldt-Rasmussen, U. Treatment of hypothyroidism in elderly patients and in patients with cardiac disease. Thyroid 2007; 16: 619.

  • 15 Gussekloo J. Thyroid Status, disability and cognitive function, and survival in old age. JAMA 2004; 292: 2591.

  • 16 Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. National Guidelines Clearinghouse 2004. www.guideline.gov.

  • 17 Jorde, et al. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. JCEM 2006; 91: 145.

  • 18 Portmann L. Obesity and hypothyroidism: myth or reality? Revue Medicale Suisse 2007; 105: 859.

  • 19 Kong, WK, et al. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am J Med. 2002; 112: 348.

  • 20 Pearce, EN. Hypothyroidism and dyslipidemia: modern concepts and approaches. Current Cardiology Reports 2004; 6: 451.

  • 21 Radetti G. et al. The natural history of euthyroid Hashimoto’s thyroiditis in children. J Pediatr. 2006; 149: 827.

  • 22 Fatourechi, Vahab. Subclinical hypothryoidism: how should it be managed? Treatments in Endocrinology 2002; 1: 211.

  • 23 Moore, DC. Natural course of ‘subclinical’ hypothyroidism in childhood and adolescence. Arch Pediatr Adolesc Med 1996; 150: 293.

  • 24 Rose, SR et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006; 117:2290.


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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: 775.

  • 26 Surks, M. Clinical manifestations of hypothyroidism. www.utdol.com.

  • 27 Ross, DS. Diagnosis of and screening for hypothyroidism. www.utdol.com.

  • 28 Ross, DS. Treatment of hypothyroidism. www.utdol.com.

  • 29 Green, GB. Hypothyroidism. Washington Manual of Medical Therapeutics. Lippincott Williams & Wilkins, Philadelphia, 2004: 489-492.

  • 30 Ross, DS. Myxedema coma. www.utdol.com

  • 31 LaFranchi, S. Acquired hypothyroidism in childhood and adolescence. www.utdol.com

  • 32 LaFranchi, S. Clnical features and detection of congenital hypothyroidism. www.utdol.com

  • 33 LaFranchi, S. Treatment and prognosis of congenital hypothyroidism. www.utdol.com



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