Pregnancy is an absolute contraindication to RAI therapy. Previously, the use of
RAI was restricted to adults older than an arbitrary age of 20 to 35 years because it
was feared that RAI could result in genetic damage or neoplasia. However, its use in
adolescents is increasing after more than 50 years of clinical experience with RAI
showing that it is safe and effective.
184–187 There is no reported evidence of genetic
I ingestion, and the dose of radiation to the gonads is <3 rads, which
is comparable to other radiographic diagnostic tests (e.g., barium enemas).
incidence of leukemia or malignancy is no higher in recipients of
thyrotoxic patients treated with drugs or surgery.
In a retrospective review of 98
adolescents followed for 36 years after receiving
I, no cancers of the thyroid or
187 One interesting finding is that patients receiving RAI
should be warned that they can set off radiation detectors at airport screening
terminals for up to 12 weeks after RAI and that they should carry documentation of
RAI is painless, effective, economical, and quick, but unsubstantiated fears about
radiation and malignancy, as well as the high incidence of hypothyroidism, may deter
its use. RAI could be used safely in this nonpregnant young patient. However, C.R.’s
prior use of iodides will dilute the
I pool. Thus, it will be impossible to achieve
therapeutic thyroid concentrations of RAI for as long as 3 to 6 months.
PROPYLTHIOURACIL VERSUS METHIMAZOLE
CASE 52-15, QUESTION 4: C.R. is started on PTU 200 mg q8h after baseline FT4
methimazole in the treatment of hyperthyroidism?
Both thioamides are effective in treating hyperthyroidism. The antithyroid
effectiveness of the thioamides primarily depends on their ability to block the
organification of iodines, thereby inhibiting thyroid hormone synthesis.
autoantibody synthesis may also be suppressed. In most hyperthyroid adults and
children, methimazole should be considered the thioamide of choice because of
increasing reports of hepatitis, some fatal, from PTU. PTU should be reserved for use
in thyroid storm, during the first trimester of pregnancy because of rare teratogenicity
from methimazole, and in those allergic to methimazole (except agranulocytosis and
hepatitis) who are not candidates for RAI or surgery.
Methimazole is effective when administered initially as a single dose compared with
the multiple-dose regimen required with PTU to achieve a euthyroid state.
Although a single-dose regimen of PTU has been tried acutely, it is most effective
when given in divided doses. Compared to PTU, methimazole is also less
hepatototoxic, less expensive, requires daily ingestion of fewer numbers of tablets,
and is not associated with a bitter tablet taste. However, PTU is preferred in thyroid
storm because, unlike methimazole, it also blocks the peripheral conversion of T4
192 Within 24 to 48 hours after PTU administration, a 25% to 40% reduction in
peripheral T3 production is seen, which contributes to PTU’s rapid onset. A
significantly greater fall in T3 concentration and the T3
in hyperthyroid patients treated acutely with PTU and iodine than with methimazole
and iodides. Lastly, PTU is preferred over methimazole during the first trimester of
CASE 52-15, QUESTION 5: Why was the thioamide therapy ineffective in C.R.? Was the dose of PTU
The inadequate response in C.R. suggests poor adherence to the thioamide dosing
regimen or a delayed response caused by prior iodide loading of the gland.
The onset of action of the thioamides is slow because they block the synthesis
rather than the release of thyroid hormone. Therefore, hormone secretion will
continue until the glandular stores of hormone are depleted. If adequate doses were
given, some improvement of clinical symptoms should be noted after 2 or 3 weeks.
The dosage of PTU is appropriate. Thioamide dosing consists of two phases:
initial therapy to achieve euthyroidism and maintenance therapy to achieve remission.
Initially, high blocking dosages of PTU (400–800 mg/day, depending on the severity
of the toxicosis) should be given in three or four divided doses, as in C.R.
Rarely, dosages of 1,200 mg/day of PTU or its equivalent may be required in patients
192 Equipotent doses of methimazole (which is 10 times
more potent than PTU on a mg-per-mg basis) can also be used. However, it is usually
unnecessary to use >40 mg/day of methimazole to restore a euthyroid state.
Toxicity is also less common (see Case 52-15, Questions 10 and 11). True resistance
to thioamides is rare; thus, most cases of unresponsiveness are caused by poor
C.R.’s adherence is also hindered by the frequency of PTU administration. The
serum half-life of PTU is short (1.5 hours), but it is the intrathyroidal drug
concentrations that should determine the dosing intervals because they are most
clearly related to the drug’s antithyroid effects.
176 PTU must be dosed every 6 to 8
hours initially, or as frequently as every 4 hours in cases of severe hyperthyroidism
and thyroid storm. In contrast, methimazole has a serum half-life of 6 to 8 hours,
remains in the thyroid for 20 hours, and has a duration of activity of up to 40
Poor adherence is often difficult to ascertain and is more likely when multiple
daily doses are required. The best option for C.R. is to change to 30 to 40 mg of
methimazole, given once daily to improve adherence, or divided into two doses to
decrease GI distress. After methimazole is given for 4 to 6 weeks to achieve
euthyroidism, the daily dosage can be reduced gradually by 25% to 30% monthly to a
dosage that maintains euthyroidism, usually 5 to 10 mg/day of methimazole. If C.R.
remains hyperthyroid despite adequate doses of thioamides, then the most likely
efficacy and toxicity of thioamides?
Before thioamides are administered, a baseline FT4 and TSH should be obtained.
A baseline white blood cell (WBC) count with differential can also help differentiate
the leukopenia associated with hyperthyroidism from drug-induced leukopenia and/or
agranulocytosis (see Case 52-15, Question 11). Baseline liver function tests can
assist in the evaluation of thioamide-induced hepatotoxicity (see Case 52-15,
Question 10). A repeat FT4 and TSH should be obtained after 4 to 6 weeks on
therapy and 4 to 6 weeks after any change in the dosing regimen. Once the patient is
euthyroid on maintenance dosages, thyroid function tests can be obtained every 3 to 6
CASE 52-15, QUESTION 7: How long should C.R. be continued on thioamide treatment?
Traditionally, thioamide therapy is continued for 1 to 2 years despite the lack of
data regarding the optimal treatment period.
164,175,176 The goal of treatment is to
control the symptoms of Graves’ disease until spontaneous remission occurs.
Graves’ disease remits spontaneously in about 30% to 50% of patients but relapse is
194 Because it is unknown when or if remission will occur, it is understandable
why the optimal duration of therapy is unclear. Short-term therapy (i.e., <6 months)
has been advocated to save time and money and improve adherence because earlier
studies suggested remission rates comparable to a longer course of therapy.
However, short-term therapy is not recommended because longer follow-ups of
patients receiving short-term therapy have noted poorer remission rates.
Most data support a 12- to 18-month course of treatment to achieve remission rates
175,176,195,196 Two prospective randomized trials found that
extending treatment from 6 to 18 months was beneficial but that 42 months of therapy
was not significantly better than 18 months.
195,196 However, one retrospective study of
patients treated for >12 months observed remission rates of only 17.5%.
conflicting results underscore the fact that determining the optimal treatment period is
confounded by the large variability that exists with regard to spontaneous remission.
Nevertheless, treatment periods of 1 to 2 years are justifiable in adherent patients.
Therapy can be reinstituted if hyperthyroidism reappears shortly after therapy is
discontinued. Methimazole can also be continued indefinitely if there are no side
effects, and treatment with either RAI or surgery is not desired. In C.R., this goal
might not be achievable, given her history of non-adherence.
CASE 52-15, QUESTION 8: Can thioamide therapy affect any of C.R.’s preexisting medical conditions?
Thyrotoxicosis can activate or intensify diabetes, primarily by increasing the basal
hepatic glucose production and the metabolism of insulin.
therapy with thioamides may restore control of C.R.’s type 2 diabetes.
C.R.’s arthritis should not be affected, although thioamides have been associated
with the development of lupus erythematosus (LE), lupus-like syndromes, and
176,199 These adverse drug reactions are rare; the incidence is <0.1%.
Lupus-like syndromes include skin ulcers, splenomegaly, migratory polyarthritis,
pleuritis and pericarditis, periarteritis, and renal abnormalities. Serologic
abnormalities may also occur with these connective tissue disorders and include
hyperglobulinemia, positive LE preparations, and positive antinuclear antibodies.
Recovery occurs with adequate steroid therapy and withdrawal of the thioamides.
Because cross-reaction between methimazole and PTU is likely to occur, patients
exhibiting these reactions should be treated with surgery or RAI. C.R.’s treatment
should be monitored with this lupus-like adverse effect in mind, but the occurrence of
this syndrome is so uncommon that a trouble-free course of therapy can be
CASE 52-15, QUESTION 9: What adjunctive therapy might help alleviate some of C.R.’s symptoms while
awaiting the onset of thioamide’s effects?
Iodides (see Case 52-15, Question 2) , β-adrenergic blocking agents without
intrinsic sympathomimetic activity, or calcium channel blockers can be used acutely
to ameliorate some of C.R.’s symptoms.
200,201 Because iodides were previously
ineffective in C.R., a β-blocker should be tried.
β-Adrenergic blocking agents rapidly decrease the nervousness, palpitations,
fatigue, weight loss, diaphoresis, heat intolerance, and tremor associated with
thyrotoxicosis, probably because many of the signs and symptoms mimic sympathetic
164,200 An increase in the number of β-adrenergic receptors rather than an
elevation in catecholamine levels is probably responsible for this overactivity.
Because the underlying disease process and thyroid hormone levels are not affected
significantly by β-blockers, patients generally remain mildly symptomatic and fail to
gain weight. For this reason, they should not be used as the sole treatment for
All β-blockers without intrinsic sympathetic activity (e.g., atenolol, metoprolol,
propranolol) are effective in alleviating the hyperthyroid symptoms, but propranolol
is the only β-blocker that significantly inhibits peripheral conversion of T4
Thyroid function tests are generally not affected except for a mild decrease in the T3
In summary, β-blockers are (a) effective adjuncts in the management of thyroid
storm, (b) useful to prepare patients for surgery, and (c) useful in the short-term
management of thyrotoxicosis during pregnancy.
180,192,200 Surprisingly, propranolol
also improves many of the neuromuscular manifestations of hyperthyroidism,
including thyrotoxic periodic paralysis. Current guidelines recommend elderly
patients, those with concomitant heart disease, and those with a resting heart rate
over 90 beats/minute receive adjunctive therapy with β-blockers.
Diltiazem or verapamil are effective alternatives when β-blockers are
201 Diltiazem 120 mg TID or QID can be tried. The dihydropyridine
calcium channel blockers are unlikely to be effective.
Because of C.R.’s history of diabetes, the effects of β-adrenergic blocking drugs
on patients with diabetes must be considered (see Chapter 53, Diabetes Mellitus). If
β-blockers are instituted, a cardioselective β-blocker would be a better choice for
on therapy that can cause hypoglycemia. The appropriate dosage should be based
on clinical and objective improvement of hyperthyroid symptoms, such as a reduction
in heart rate. Metoprolol 25 to 50 mg BID can be started initially and the dosage
titrated to maintain the heart rate at <90 beats/minute. Otherwise, diltiazem,
verapamil, or a retrial of iodides is warranted.
CASE 52-15, QUESTION 10: A pruritic area over the pretibial aspects of both legs as well as several
maculopapular erythematous patches and abdominal tenderness were noticed during C.R.’s physical
examination. Do these reactions require the discontinuation of her PTU?
Although C.R. may be experiencing a drug rash from PTU, pretibial myxedema or the
dermopathy of Graves’ disease may also be possibilities because of the location of
the pruritic area. About 4% of patients with Graves’ disease who exhibit infiltrative
exophthalmos also have dermatologic changes. The skin is thickened, erythematous,
and non-pitting because of mucopolysaccharide infiltration and accentuation of hair
follicles. Pruritus or pain may be present. Treatment includes topical corticosteroids,
control of the Graves’ disease, and reassurance.
Thioamides can produce a maculopapular pruritic rash in 5% to 6% of treated
176 The rash can occur at any time but is more common early in therapy. If the
rash is mild, drug therapy can be continued while the patient’s symptoms are treated
with an antihistamine and a topical steroid; such rashes generally subside
is urticarial in nature or associated with systemic manifestations (e.g., fever,
C.R.’s symptoms of nausea, vomiting, diarrhea, fatigue, and abdominal tenderness
require further evaluation. Her symptoms could be consistent with mild GI side
effects from her PTU therapy, impending thyroid storm from non-adherence (see Case
52-22, Question 1) or more seriously, PTU-induced hepatitis. PTU has been
associated with 0.1% severe hepatotoxicity, leading to liver transplants and fatalities
30,169,202,203 Although usually hepatocellular in nature, cholestasis,
hepatic necrosis, and fulminant hepatic failures have been reported.
elevations in transaminases occur in approximately 30% of asymptomatic patients
within the first 2 months of PTU therapy and may not require drug discontinuation.
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