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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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Katherine Stanley, MD

January 14, 2008

  • 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
  • Overt 0.1-2% of adults
  • 2% of adolescents (subclinical and overt)
  • 5-8x more common in women
  • Congenital HT in 1:4000 newborns
clinical manifestations
Clinical Manifestations
  • Constitutional
    • Fatigue, weight gain, cold intolerance
  • Skin
    • Coarse hair and skin, brittle nails, puffy facies, nonpitting edema
    • Enlargement of tongue, periorbital edema, hoarseness
clinical manifestations5
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
clinical manifestations6
Clinical Manifestations
  • GI
    • Constipation
  • Heme
    • Normocytic anemia, macrocytic anemia (pernicious), hypocoagulable state, incr LDH
  • Renal
    • Hyponatremia, increased creatinine
clinical manifestations7
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
a few words about myxedema coma
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
clinical manifestations in children
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
other reasons to check the tsh
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
causes of hypothyroidism
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
hypothyroidism in childhood cancer survivors
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
  • 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
tricky thyroid when tsh doesn t work
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
drugs and thyroid testing
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
to screen or not to screen
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
to screen or not to screen17
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
  • 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
treatment in children
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
start low go slow
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
  • 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
what brand should i use
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
what if my patient won t take their synthroid
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
what if my pt wants more synthroid
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
special cases cardiac disease 14
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
special cases elderly
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
special cases subclinical 16
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
what if i have sht and
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
subclinical hypothyroidism in children 21
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
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
special cases congenital hypothyroidism
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
congenital ht 24
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
congenital ht
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
special cases drugs affecting treatment
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
special cases surgery
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

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

  • 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.
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