Hypothyroidism: Diagnosis and Treatment in Adult Women

Hypothyroidism:
Diagnosis and Treatment
in Adult Women
Cheryl Rosenfeld, DO, FACE, FACP
Clinical Assistant Professor of Medicine
Touro College of Osteopathic Medicine
Middletown, NY
North Jersey Endocrine Consultants
Denville, NJ
Objectives
•  Understand how to use laboratory testing to diagnose thyroid
disease in adult women, pregnant women and elderly women
•  Recall appropriate thyroid hormone replacement, with special
considerations in pregnant women and elderly women
•  Recognize treatment goals for hypothyroidism in adult women,
pregnant women and elderly women
Primary Hypothyroidism: Causes
• Autoimmune
• Hashimoto’s thyroiditis
•  Iatrogenic
•  Surgery, radioiodine, external beam radiation
•  Congenital
•  Agenesis, dyshormonogenesis, TSH-R mutation
•  Iodine deficiency
•  Infiltration
•  Amyloid, Riedel’s
Hashimoto’s Thyroiditis
• Autoimmune process is gradual
•  Gradual reduction in thyroid function
•  Compensation period, TSH rises to keep thyroid hormone
levels normal
•  Subclinical hypothyroidism – patients may or may not
have symptoms
• Some patients never develop hypothyroidism
Secondary Hypothyroidism: Causes
•  Hypopituitarism
•  Tumor, radiation, surgery, infiltration, Sheehan’s, trauma, genetic
•  Isolated TSH deficiency or inactivity
•  Hypothalamic disease
•  Tumor, trauma, infiltration, idiopathic
Kocher, 1909 Nobel Prize Lecture
“…the dullness and the mental and physical sluggishness and
incapacity, which in fully developed cases is sufficiently striking …
especially if the bloated face is added to a stupid expression. But the
degree of dullness varies considerably. In general the patients do not
feel really ill, but merely have the feeling of something inhibiting them
in everything they want to undertake - the effect being greater the
more mentally active and alert they used to be. With the best will in the
world they can no longer perform any sort of sustained mental work,
they cannot read, write nor converse for long, and hence prefer to be
silent and withdraw from society. Speech becomes slow and laborious
and answers have to be waited for. The decline in memory is quite
especially burdensome.”
Screening vs. Diagnosis
•  Screening
•  Thyroid function testing in asymptomatic patients who are at risk for
disease and are not known to have disease
•  Who to screen: hyperlipidemia, hyponatremia, elevated CK, macrocytic
anemia, effusions (pleural or pericardial), history of thyroid injury
(surgery, radiation), pituitary or hypothalamic disease, autoimmune
disease, medications that alter thyroid function (amiodarone, lithium,
TKIs, interferon)
•  Diagnosis
•  Thyroid function testing in patients who have symptoms of the disease
Diagnosis of Hypothyroidism in Adult
Women
Signs and Symptoms
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Fatigue, weakness
Dry skin
Cold intolerance
Hair loss
Poor concentration/memory
Constipation
Weight gain
Dyspnea
Hoarseness
Menorrhagia
Paresthesias
Hearing impairment
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Dry, coarse skin
Dry, brittle hair
Cool extremities
Puffy face, hands, feet
Hair loss, alopecia
+/-Goiter
Bradycardia
Peripheral edema
Delayed tendon reflex relaxation
Carpal tunnel syndrome
Yellow tinged skin
Effusions
Systemic Effects of Hypothyroidism
•  Cardiac
•  Decreased myocardial contractility
•  Decreased pulse rate
•  Increased peripheral resistance –
diastolic hypertension
•  Pericardial effusions
•  Hypercholesterolemia
•  Pulmonary
•  Pulmonary function usually normal
•  Impaired respiratory muscle
function
•  Decreased ventilatory drive
•  Sleep apnea
•  Pleural effusions
•  Genitourinary
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Decreased libido
Oligo/amenorrhea
Decreased fertility
Increased risk of miscarriage
Risk to fetus – impaired intellectual
function if mother untreated
hypothyroid
•  Musculoskeletal
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Carpal tunnel syndrome
Muscle stiffness, cramps, pain
Slow relaxation of tendon reflexes
Memory/concentration impaired
Rarely: ataxia, psychosis, dementia
Hypothyroidism: Lab
•  Primary hypothyroidism
•  TSH increased
•  T4 decreased
•  T3 decreased
•  T3RU decreased
•  Subclinical hypothyroidism
•  TSH sl. increased, T4 normal
•  Secondary hypothyroidism
•  TSH low or inappropriately normal, T3 &T4 low
A word about imaging…
Do a really
good physical
examination -
A gland with
Hashimoto’s thyroiditis
may feel slightly
enlarged or firm.
• If you see or feel
something abnormal,
then order an
ultrasound of the
thyroid
• No rationale to
• Image every patient
with hypothyroidism
• Order radioiodine
imaging in
hypothyroidism
Photo courtesy of Jeremy
Goodman, DVM
Diagnosis of Hypothyroidism in Pregnant
Women
Recommended TSH Reference Ranges
in Pregnancy
First Trimester
Second Trimester
Third Trimester
0.1-2.5 mIU/L
0.2-3.0 mIU/L
0.2-2.0 mIU/L
Measure Total T4 due to effect of alterations in serum proteins.
Result should be 1.5 fold the non-pregnant range.
Stagnaro-Green A, et al. Thyroid, 2011.
Garber, JR, et al. Endocrine Practice, 2012.
Here is the controversy regarding
screening…
Associations Between Thyroid Disease
and Adverse Pregnancy Outcomes
•  Stagnaro-Green, et al. JAMA 1990: 552 women screened for
thyroid autoantibodies in first trimester, detectable antibodies
significantly correlated with increased rates of miscarriage –
17% vs. 8.4%
•  Haddow, et al. NEJM 1999: Compared IQ scores of offspring of
62 women with above normal TSH during pregnancy (13.2+0.3)
to offspring of 124 control women (1.4+0.2), found that IQ
scores were 7 points lower in children of women with abnormal
TSH during pregnancy
Recent Literature Regarding Thyroid
Disease and Pregnancy
•  Cleary-Goldman, et al. Obstetrics and Gynecology 2008: 10,990
patients, although hypothyroxinemia was associated with preterm
labor and macrosomia in 1st trimester and gestational diabetes in
second trimester and positive antibodies were associated with
premature rupture of membranes, there was no consistent pattern
of adverse outcomes
TSH
•  Negro, et al. JCEM 2010: 4562 patients, no significant difference
between case finding and screening groups with regard to
2.5
adverse outcomes
•  Lazarus, et al. NEJM 2012: 21,846 women provided blood samples,
390 in screening group (obtained immediately) and 404 in control
group (serum stored and run after delivery) with either high
TSH or
TSH
low free T4, antenatal screening and maternal treatment for
hypothyroidism did not improve cognitive function in 3.5
children
ACOG Recommendations
•  Untreated overt hypothyroidism harmful to a woman and her fetus
•  TSH and T4 should be measured to diagnose thyroid disease in pregnancy
•  Overt thyroid disease should be treated
•  Do not perform universal routine screening for thyroid disease
in pregnancy – Level A recommendation
•  Studies suggesting association between subclinical hypothyroidism in
pregnancy and impaired neurodevelopment in offspring remain an association
•  New studies have had mixed results
•  A large randomized trial showed no difference in cognitive function in 3 year
old children of mothers randomized to screening and treatment versus no
treatment for subclinical hypothyroidism
Diagnosis of Hypothyroidism in Elderly
Women
“At autopsy, it is almost impossible to find
a normal thyroid gland in a woman over
50 years of age.”
TSH Distribution by Age Group – Disease
Free Population
Subclinical thyroid dysfunction is not
associated with depression, anxiety
or change in cognition in the elderly.
Roberts L, et al. Annals of Internal Medicine, 2006
Surks and Hollowell, JCEM, 2007
Treatment of Hypothyroidism
Strong Recommendation
“Levothyroxine is recommended as the preparation
of choice for the treatment of hypothyroidism due
to its efficacy in resolving the symptoms of
hypothyroidism, long-term experience of its
benefits, favorable side effect profile, ease of
administration, good intestinal absorption, long
serum half life and low cost.”
Jonklaas J, et al. Thyroid, 2014.
Thyroid Hormone Secretion, Action and
Metabolism
•  Thyroid hormone action
•  Determines growth and development
•  Critical role in regulating function and metabolism of virtually every
organ system
•  Control is complex and redundant
•  T4 is a prohormone, peripherally converted into T3, the
active metabolite
•  Activating conversion – Type 1 and type 2 deiodinases (D1 and D2)
•  Inactivating conversion – Type 3 (D3)
•  Thyroid hormone is carried into the cell by transporters, which
maintain intracellular concentrations
Thyroid Hormone Conversion:
Deiodinases
•  Type I
•  Predominantly liver and kidney, smaller extent in thyroid
•  Responsible for 24% of circulating T3
•  Upregulated by T3
•  Type II
•  Pituitary, brain, brown fat, heart, skeletal muscle, thyroid
•  Local regulation of T3 concentration
•  Responsible for 60% of circulating T3
•  Type III
•  Brain and skin
•  Inactivates T4 and T3 (source of reverse T3)
•  Its role is to clear T3
T3 is More Important at the Cellular Level
Than in the Bloodstream
•  Treatment of hypothyroidism with thyroxine monotherapy leads
to higher serum T4 and lower serum T3 than euthyroid state
•  T3 first accumulates in the cell (intracrine tissue specific effect)
•  T3 then exits the cell (paracrine effect on surrounding tissues +
plasma pool)
•  Thyroid hormone enters cells via transporters
•  Transporters control intracellular levels of T3
•  Found in liver, kidney, brain and heart
Thyroid Hormone Metabolism
•  Extensively bound to plasma proteins
•  Thyroxine binding globulin (TBG)
•  Transthyretin (TTR) - thyroxine binding prealbumin
•  Albumin
•  Free hormone biologically active
•  Binds to nuclear receptor
•  Half life of thyroid hormone
•  T4 – 7 days
•  T3 – 18 hours
Thyroid Hormone Replacement
•  Consider age, comorbidities and level of thyroid dysfunction
•  Adult women:
•  1.6 mcg/kg body weight daily dose
•  Target TSH = normal range
•  Pregnant women:
•  Typically need an increase in dose early in the first trimester
•  Target TSH <2.5
•  Must use LT4, the developing fetus cannot use T3!!!!
•  Elderly women
•  Start low, go slow (although there are studies to indicate starting full
replacement dose in patients without heart disease)
•  12.5-25 mcg daily with gradual increases as tolerated, per TSH levels
Brand vs. Generic
Try to maintain the patient on
the same brand or generic
preparation.
Hypothyroidism: Treatment
Considerations
•  Initial effects seen in 3 to 5 days - this does not mean that the
patient will feel normal yet
•  ½ life is 7 days – steady state will not be reached for 4-5 weeks
•  Thyroid function testing should be done no sooner than 4-6
weeks after initiation of therapy or dose change
•  Normalize free T4 in secondary (pituitary) hypothyroidism
•  Absorption affected by antacids, iron, sucralfate and bile acid
sequestering agents
•  Intravenous therapy only if patient NPO or has myxedema coma
Treatment Goals
What are we trying to accomplish?
• Resolution of hypothyroid signs and symptoms
• Normalize TSH (with improvement in thyroid hormone
concentrations)
• Avoid overtreatment – especially in elderly patients!
Determining Thyroid Hormone Replacement
Adequacy in Patients with Primary
Hypothyroidism
Use the TSH,
you must!
“symptoms alone lack
sensitivity and specificity and
are not recommended for
judging adequacy of
replacement in absence of
biochemical assessment.”
Jonklaas J, et al. Thyroid, 2014.
Summary
•  Screen adults at risk for hypothyroidism
•  Universal screening not recommended in pregnancy
•  Use appropriate thyroid testing to diagnose patients with suspected
disease
•  Be aware of different normal ranges in pregnancy and elderly
patients
•  TSH is the best guide in patients with primary hypothyroidism (intact
pituitary and hypothalamus)
•  Use T4 in patients with secondary hypothyroidism
•  Explore non-thyroidal illness in patients who have symptoms and
normal TFTs or adequate replacement