The management of subclinical hyperthyroidism is controversial, especially in
asymptomatic patients because of limited treatment outcomes evidence.
guidelines recommend treatment of subclinical hyperthyroidism (TSH levels <0.1
microunits/mL) in patients >65 years, postmenopausal woman not taking
antiresorptive therapy (see Chapter 110, Osteoporosis), and those with cardiac
34,87,88 For patients with TSH levels of 0.1 to 0.45
microunits/mL, treatment of patients >65 years of age and those with cardiovascular
disease or hyperthyroid symptoms can be considered.
RAI or thioamide therapy only if the TSH level is <0.1 microunits/mL in
postmenopausal women, in those 60 years or older, and in patients with a history of
heart disease, osteoporosis, or hyperthyroid symptoms.
levels of 0.1 to 0.4 microunits/mL, treatment can be considered if they are in the
aforementioned groups; otherwise, therapy is not recommended because TSH
In J.C., his thyroid function tests should be repeated. An RAIU and scan should be
obtained to detect any hyperactive areas or nodules that might be responsible for the
suppressed TSH. Because J.C. is generally healthy, treatment can be considered if
there are concerns about cardiac disease or bone loss; otherwise, no therapy is
reasonable based on the available evidence. Close monitoring of thyroid function
tests is recommended every 6 months to 1 year. If hyperthyroid symptoms or changes
in cardiac or bone function occur, then RAI therapy is recommended.
QUESTION 1: N.N., a 32-year-old woman who is 3 months pregnant, is referred for management of her
Graves’ disease. What are the therapeutic ramifications of managing thyrotoxicosis during pregnancy?
Hyperthyroidism develops in 0.02% to 1.4% of pregnant women and often
217 Symptoms of thyrotoxicosis are typically ameliorated during
the second and third trimesters and exacerbated early in the postpartum period.
Treatment is crucial to prevent damage to the fetus and to maintain the pregnancy.
RAI, chronic iodide therapy, and iodine-containing compounds are contraindicated
during pregnancy because they will cross the placenta to produce fetal goiter and
217–219 As little as 12 mg/day of iodide has produced neonatal goiter and
death. The long-term use of β-adrenergic blockers should also be avoided because it
is associated with fetal respiratory depression, a small placenta, intrauterine growth
retardation, impaired response to anoxia, and postnatal bradycardia and
should be limited to transient preoperative use prior to thyroidectomy or in the
Either surgery or thioamide is the treatment of choice for pregnant hyperthyroid
patient. Surgery is safe during the second trimester with adequate preoperative
preparation. During other trimesters, thioamides are preferred because surgery can
precipitate spontaneous abortion. PTU is preferable during the first trimester because
of rare reports of teratogenicity from methimazole, but methimazole is preferred
thereafter to reduce the risks of PTU-associated hepatitis. Both thioamides are
221 demonstrate similar placental crossing properties,
produce similar thyroid hormone concentrations in fetal umbilical cord blood
223 Methimazole has been associated with anecdotal reports of congenital
scalp defects (e.g., aplasia cutis) and an embryopathy syndrome (esophageal and
224–227 However, the risks of reversible aplasia cutis were not greater
in women receiving methimazole (e.g., 2.7%) compared to PTU (e.g., 3%) or
hyperthyroid controls (e.g., 6%).
221,224,225 Therefore, methimazole can be considered
throughout pregnancy if there is intolerance or non-adherence to PTU217,218,221
Chapter 49, Obstetric Drug Therapy).
Fetal hypothyroidism and goiter can develop when large doses of thioamides are
administered to the mother, even if the mother is still hyperthyroid.
avoid goiter and suppression of the fetal thyroid gland, which begins to function at
about 12 to 14 weeks of gestation, the lowest effective thioamide dose should be
levels occur in >90% of neonates when maternal FT4
maintained in the upper third of the normal range (1.5–1.9 ng/L).
over 30% of neonates exhibit a low FT4 when maternal levels are maintained in the
lower two-thirds of the normal range.
105 Control of maternal hyperthyroidism
increases the risk of fetal hypothyroidism. Start PTU (e.g., maximum of 300 mg/day
in three divided doses) or methimazole (e.g., maximum of 20–30 mg given once
daily) until control is achieved, then taper PTU to 50–150 mg/day, and after the first
trimester, change to 5 to 15 mg/day of methimazole for the remainder of the
pregnancy. In many patients, remission
of Graves’ disease occurs during pregnancy, and some patients can discontinue
thioamides in the second half of pregnancy.
217 Measurement of TRAb levels between
weeks 22 and 26 of gestation can be useful, because disappearance of TRAb
indicates that thioamide therapy may no longer be necessary.
thioamides provide satisfactory control of maternal hyperthyroidism and should not
cause clinically evident neonatal thyroid dysfunction. Patients requiring more than the
maximum recommended thioamide dosages for control may need to consider the
possibility of surgery in the second trimester.
Nevertheless, a small but significant reduction in neonatal serum T4 occurs even
when small (100–200 mg) doses of PTU are administered during pregnancy to
It is unclear whether this mild, transient
reduction in serum T4 causes long-term impairment of mental development or is
otherwise detrimental to the newborn. To date, no significant differences in
intellectual development have been noted between children exposed to PTU or
methimazole in utero and their unexposed siblings.
228–230 However, children exposed
in utero to >300 mg/day of PTU had lower IQs.
Although transient fetal or neonatal hypothyroidism does not appear to be a major
threat to the baby, it is advisable to maintain the mother in a mildly hyperthyroid
217,218 Mild maternal hyperthyroidism appears to be well tolerated, but maternal
hypothyroidism is poorly tolerated by both the mother and the fetus (see Case 52-8,
levels should be maintained in the upper third of the normal range to
decrease the risk of fetal hypothyroidism because normal thyroid function tests are
suggestive of hypothyroidism during pregnancy (high TBG and TBPA levels). The
goal of therapy is a suppressed maternal TSH level (0.1–0.4 microunits/mL) because
complete correction maternal hyperthyroidism increases the risk of fetal
It is not rational to add thyroid hormone to the mother’s regimen to prevent fetal
goiter or hypothyroidism because thyroid hormones do not reach the fetal circulation.
Thyroid supplementation only complicates the treatment of maternal hyperthyroidism
by increasing thioamide requirements, which can further compromise fetal thyroid
If the mother has not been thyrotoxic throughout pregnancy, a
normal infant can be expected. All pregnant patients with a history of or active
Graves’ disease should be screened with a TSI during pregnancy to assess the risk of
217 Neonatal Graves’ disease occurs in 1% to 5% of infants
born to mothers with the disease; therefore, all newborns should be evaluated for the
105,220 Lastly, both thioamides can be safely used in the lactating mother if
the maximal dose of methimazole does not exceed 10 to 20 mg daily or less
preferably, if PTU does not exceed 200 mg/day (up to 750 mg/day in one
231,232 Propranolol and iodides are secreted in breast milk and should be
avoided (see Chapter 49, Obstetric Drug Therapy).
Treatment with Radioactive Iodine
QUESTION 1: B.J., a 35-year-old woman, has newly diagnosed Graves’ disease complicated by CHF and
therapy on the efficacy of her RAI therapy.
Older or debilitated patients with severe hyperthyroidism and/or concomitant
cardiac disease should receive antithyroid pretreatment before RAI therapy to
deplete stored thyroid hormone and minimize post-RAI hyperthyroidism (occurring in
I administration) and thyroid storm caused by leakage of
hormones from the damaged thyroid gland.
176,192,233 Other hyperthyroid patients can
receive RAI safely without pre-therapy.
Lugol’s solution or other iodides should not be given before RAI because iodides
decrease the gland’s uptake of RAI and its effectiveness. This effect of iodides
persists for several weeks. Iodides can be given 1 to 7 days after RAI treatment if it
is needed to rapidly control symptoms of hyperthyroidism.
Prior to RAI, thioamides achieve a euthyroid state, but pretreatment may lower the
cure rate and increase the need for subsequent RAI.
176,184,234 A meta-analysis of 14
trials found that use of thioamides (e.g., PTU, methimazole, carbimazole) before and
after RAI was associated with an increased risk of treatment failure (relative risk of
1.28; 95% CI, 1.07–1.52) and a 32% reduced risk of hypothyroidism regardless of
184 To facilitate optimal uptake and retention of
gland, thioamides should be stopped at least 2 to 3 days, before RAI
If necessary, thioamides can be restarted 3 to 7 days after RAI
administration without impairing its efficacy. β-Adrenergic blocking agents can be
used before, during, and after RAI therapy without interfering with its uptake.
B.J. remains symptomatic because methimazole and iodides decreased RAI’s
efficacy. Propranolol should be given to B.J. before RAI therapy to relieve
hyperthyroid symptoms because only a short course of thioamide was given. Iodides
might be preferable to propranolol following RAI therapy if B.J.’s CHF worsens.
For subsequent RAI doses, methimazole pretreatment should be stopped 2 to 3 days
before RAI, thereby allowing a shorter duration of hyperthyroidism.
CASE 52-19, QUESTION 2: B.J. is still symptomatic 2 weeks after a second dose of RAI. When can she
Although some benefits from RAI therapy are evident within 1 month, a period of 6
to 18 weeks is generally required for maximal effects.
164,184,233 Euthyroidism or, more
commonly, hypothyroidism occurs in approximately 80% to 90% of patients treated
with a single nonablative dose of RAI; the remaining 10% to 20% become euthyroid
or hypothyroid after two or more doses. This slow onset is a disadvantage, but
symptomatic control can be obtained quickly by administration of a β-adrenergic
blocking agent, or iodides starting 1 to 14 days after the
preferable if a second dose of RAI is necessary. Thioamides can also be given,
although their therapeutic effects are delayed for 3 to 4 weeks.
At least 3 months should elapse before a second dose of RAI is administered, and
most recommend waiting 6 months before repeating RAI, unless the patient remains
severely thyrotoxic. It is inadvisable to give a second dose before the major effects
of the first dose have become apparent. Although the use of iodides before RAI in
B.J. may have decreased the amount of
I retained by her thyroid, it is still
advisable to wait at least 3 months before a second dose is given.
Safety precautions are not universal and vary across the United States depending
on the dose of RAI administered.
184 B.J. should avoid close contact (e.g. 6 ft) with
children for 5 days, with pregnant women for 10 days, and intimate contact with body
fluids for 5 days. B.J. should avoid airplane travels, public transportation, and work
if contact with others during these activities last more than 2 hours. Other
recommendations include sole use of bathroom facilities; sitting while urinating to
avoid splashing and to flush the toilet twice with the lid down.
and dry. What is a likely explanation for her symptoms?
S.D.’s clinical presentation and history are compatible with hypothyroidism
secondary to RAI therapy. A FT4 and a TSH level would confirm this diagnosis.
Iatrogenic hypothyroidism is the major complication of RAI therapy, although
transient hypothyroidism can occur in the first 3 to 6 weeks after therapy.
incidence of iatrogenic myxedema is often reported as 7% to 8%, but it increases at a
constant rate of 2.5% per year. The reported prevalence of this complication ranges
from 26% to 70% after 1 to 14 years.
The best predictor of eventual hypothyroidism is the total dose of RAI
administered. Prevention of iatrogenic hypothyroidism is directed toward calculation
of a dose that will produce neither recurrent hyperthyroidism nor hypothyroidism.
Unfortunately, when lower doses of RAI were used to avoid hypothyroidism, the cure
rate was reduced but the incidence of hypothyroidism was unaffected. Thus, the
appearance of iatrogenic hypothyroidism may be inevitable with time. However,
hypothyroidism is managed easily and is an acceptable therapeutic end point.
Because hypothyroidism after RAI therapy is latent and often insidious, patients
should be informed of this and monitored closely at monthly intervals for subsequent
hypothyroidism. Awareness of a transient hypothyroidism soon after RAI therapy
should minimize the institution of unnecessary hormone replacement.
H.R.’s ocular changes with Graves’ disease?
H.R. presents with symptoms consistent with the infiltrative ophthalmopathy of
237–239 The eye signs of Graves’ disease are the most striking
abnormality of this disorder. Rarely, ophthalmopathy can occur without any evidence
of hyperthyroidism. Fortunately, severe ophthalmopathy occurs in only 3% to 5% of
patients, while 25% to 50% have some eye findings. Eye disease is more severe in
older patients and in men than women. Smokers often have higher levels of TSI and
It is unknown why the eye and its muscles are attacked in Graves’ disease but is
likely related to the presence of TSH receptor antibodies found in patients with
239 Histologic examination reveals lymphocytic infiltration, increased
mucopolysaccharides, fat (because of increased adipogenesis and
glycosaminoglycans), and water in all retrobulbar tissue. Ocular symptoms include
edema, chemosis, excessive lacrimation, photophobia, corneal protrusion
(proptosis), scarring, ulceration, extraocular muscle paralysis with loss of eye
movements, and blindness from retinal and optic nerve damage.
Common Skin Disorders. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)
The eye involvement can occur at any time and is usually bilateral. The ocular
symptoms usually subside or remain stable once the patient is euthyroid; however,
some cases will progress during the euthyroid period or following RAI treatment of
the hyperthyroidism (see Case 52-21, Question 2). Pioglitazone has been associated
with a 1 to 2 mm increase in eye protrusion by stimulating adipogenesis and
increasing retrobulbar fat production.
241 While eye changes were more common in
people with a history of thyroid disorders, the overall incidence of eye changes
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