Transcript Hypothyroidism for the Primary Care Provider

Hypothyroidism
Katherine Stanley, MD
January 14, 2008
Definitions
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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
Epidemiology1
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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
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Constitutional
– Fatigue, weight gain, cold intolerance
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Skin
– Coarse hair and skin, brittle nails, puffy facies,
nonpitting edema
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HEENT
– Enlargement of tongue, periorbital edema,
hoarseness
Clinical Manifestations
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Cardiovascular
– Bradycardia, decreased contractility,
increased SVR->incr diastolic BP,
increased cholesterol (2x the general
population)2, increased homocysteine,
pericardial effusions
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Respiratory
– DOE, rhinitis, decreased exercise capacity,
OSA (macroglossia), pleural effusions
Clinical Manifestations
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GI
– Constipation
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Heme
– Normocytic anemia, macrocytic anemia
(pernicious), hypocoagulable state, incr
LDH
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Renal
– Hyponatremia, increased creatinine
Clinical Manifestations
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Reproductive
– Menstrual irregularities, decreased fertility, incr
prolactin, decr libido, ED, delayed ejaculation
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Musculoskeletal
– Delayed DTRs, myalgias, arthralgias, incr CK,
carpal tunnel
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Neurologic
– Depression, dementia, Hashimoto’s
encephalopathy, myxedema coma
A few words about
myxedema coma
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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
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Most common manifestation is declining growth
velocity, short stature
– Generally insidious
– May be only symptom
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Altered school performance
– May actually improve in some children
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Delayed pubertal development
Enlarged sell turcica 2/2 hyperplasia of thyrotroph
cells
– Rarely symptomatic
– Reversible with therapy
Other reasons to check
the TSH
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Goiter
Surgery around the thyroid
Irradiation
Drugs that affect thyroid
– Lithium, amiodarone
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Autoimmune diseases
– DM 1, pernicious anemia, vitiligo, primary
adrenal insufficiency, PBC
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Chromosomal disorders, eg Down’s,
Turner’s, Klinefelter’s
Causes of Hypothyroidism
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Chronic autoimmune thyroiditis
(Hashimoto’s)
– Most common cause in both children and adults
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Thyroidectomy
– 2-4 weeks with total, variable with subtotal
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Neck irradiation
Radioiodine therapy
Iodine- deficiency or excess
Drugs
– Lithium, amiodarone, kelp, IFN-a, IL-2, contrast
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Infiltrative disease
Hypothyroidism in
Childhood Cancer Survivors
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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
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May be some risk from chemo alone
– 30% of the patients in above study had not
received any radiation
Diagnosis
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Check the TSH
– 98% sensitive, 92% specific
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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
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If TSH increased, check free T4
Tricky Thyroid- when TSH
doesn’t work
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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
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Drugs that affect Thyroid Testing
– See next slide
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Don’t forget about sick euthyroid
Drugs and Thyroid
Testing
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Decreased TSH secretion
– Glucocorticoids, dopamine
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Decreased TBG
– Glucocorticoids, androgens, niacin
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Increased TBG
– Estrogens, tamoxifen, methadone, heroin,
clofibrate
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Increased T4 clearance
– Phenytoin, carbamazepine, rifampin,
phenobarbital
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Decreased T4 binding to TBG
To screen or not to
screen?
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American Thyroid Association recommends
universal screening q5yrs beginning at 355
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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
screen?
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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
Treatment
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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
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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
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Avoid overtreatment
– Maintain TSH in lower nl range, T4 in upper normal
– Can cause craniosynostosis in infants, deleterious effects
on behavior, school performance, growth
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May spontaneously remit, but should continue
treatment until complete growth and puberty
Start low, go slow?
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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
So…
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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?
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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?
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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?
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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
14
Disease
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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
Special Cases-Elderly
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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
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?Survival benefit
Special Cases16
Subclinical
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TSH 4.5-10, no treatment
– Rate of progression 2.6% Ab-, 4.3% Ab+
– Monitor TSH q6-12 mos
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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
…?
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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 children21
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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
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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
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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 HT24
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Clinical Manifestations
– Lethargy, slow movement, hoarse cry, feeding difficulties,
constipation, macroglossia, umbilical hernia, large
fontanels, hypotonia, dry skin, hypothermia, prolonged
jaundice
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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
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Treatment
– Oral T4 (crushed pills)
– 10-15 mcg/day
– Avoid soy formula
Congenital HT
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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
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Drugs that affect TBG or binding of T4
to TBG
– I already told you
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Drugs that decrease absorption of T4
– Cholestyramine, CaCO3, FeSO4,
sucralfate, PPIs, and others
Special Cases- Surgery
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Higher incidence of ileus, hypotension,
hyponatremia, CNS dysfunction
Consider postponing elective surgeries
Not urgent surgeries, just be aware of
slightly increased complications
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
References
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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
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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.
References
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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
Questions?