Hypothyroidism

1
Hypothyroidism

• Katherine Stanley, MD
• January 14, 2008

2
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

3
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 14000 newborns

4
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
• 
  
  

5
Clinical Manifestations

• Cardiovascular
• Bradycardia, decreased contractility, increased
  SVR-gtincr diastolic BP, increased cholesterol (2x
  the general population)2, increased homocysteine,
  pericardial effusions
• Respiratory
• DOE, rhinitis, decreased exercise capacity, OSA
  (macroglossia), pleural effusions

6
Clinical Manifestations

• GI
• Constipation
• Heme
• Normocytic anemia, macrocytic anemia
  (pernicious), hypocoagulable state, incr LDH
• Renal
• Hyponatremia, increased creatinine

7
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, Hashimotos encephalopathy,
  myxedema coma

8
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

9
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 Downs, Turners,
  Klinefelters

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Causes of Hypothyroidism

• Chronic autoimmune thyroiditis (Hashimotos)
• 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

12
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

13
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 doesnt 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
• Dont forget about sick euthyroid

15
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

16
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

17
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

18
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

19
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

20
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

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 FTI10
• However, FDA recommends remaining on same
  preparation, checking TSH after 6 wks if pt must
  change11

23
What if my patient wont take their Synthroid?

• T4 has very long half life
• Can give total weekly dose qwk12
• 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
• 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

25
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 MM with tx of
  hypothyroidism
• Some evidence of increased CV MM 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

26
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

27
Special Cases- Subclinical16

• TSH 4.5-10, no treatment
• Rate of progression 2.6 Ab-, 4.3 Ab
• Monitor TSH q6-12 mos
• TSH gt10, 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

29
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

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Special Cases-Pregnancy

• Increased TBG, T4 clearance, and transfer of T4
  to fetus
• Increased requirement begins _at_ 8 wks, plateaus _at_
  wk 16
• 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
• 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

33
Congenital HT

• Prognosis
• Normal growth, development, and intelligence if
  treated early (lt2 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

35
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 Childrens 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
  Administrations decision regarding
  bioequivalence of levothyroxine sodium. Thyroid
  2004 14486.
• 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
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• 21 Radetti G. et al. The natural history of
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  Pediatr. 2006 149 827.
• 22 Fatourechi, Vahab. Subclinical
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  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 1172290.

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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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Questions?