Liver enzymes usually normalize within 3 months of reducing the PTU to maintenance
dosages despite drug continuation. However, PTU should be stopped immediately in
patients with clinical symptoms of hepatitis to ensure complete recovery. The
mechanism of PTU-induced hepatotoxicity appears to be autoimmune because
circulating autoantibodies and in vitro peripheral lymphocyte sensitization to PTU
170 Overt hepatitis typically occurs during the first 2 months of
PTU therapy and is not dose related. In contrast, methimazole rarely produces a
cholestatic jaundice picture that might be more common in older patients and in those
receiving higher dosages (i.e., >40 mg/day).
In patients with thioamide-induced
hepatitis, changing to the alternative thioamide is not recommended because fatalities
have been reported on rechallenge. In such patients, either radioactive therapy or
In C.R., PTU should be stopped while awaiting results of thyroid function tests,
transaminases, and bilirubin. Routine monitoring of liver function tests is not
recommended during thioamide therapy because patients can be asymptomatic.
However, routine monitoring might be reasonable in patients with a history of liver
disease and risk factors for hepatitis (e.g., alcohol use). All patients receiving
thioamides should be questioned closely during the first 2 months of therapy for
symptoms of hepatitis, and hepatic function tests should be obtained if appropriate.
CASE 52-15, QUESTION 11: Assess C.R.’s complaints of sore throat and cough.
C.R.’s complaints should not be dismissed casually because they might indicate
PTU-induced agranulocytosis. Agranulocytosis (<500/mm3 of neutrophils) is the most
severe adverse hematologic reaction associated with the thioamides and should be
In contrast, drug-induced leukopenia is usually
transient, is not associated with impending agranulocytosis, and is not an indication
to discontinue thioamide therapy. An accurate history should be obtained from C.R.
The clinician should be particularly alert for a temperature of 101°F for 2 or more
days, malaise, or other flu-like findings that appeared temporally with her sore
throat. If subjective or objective data are consistent with agranulocytosis, the PTU
should be discontinued immediately until the results of a repeat WBC count with a
differential are obtained. Traditionally, routine serial determinations of WBC counts
are not recommended for monitoring the development of agranulocytosis because the
onset is so abrupt. Instead, patients should be instructed to immediately report rash,
fever, sore throat, or any flu-like symptoms. However, one study suggested that
weekly monitoring of the WBC count with a differential during the first 3 months of
antithyroid therapy might identify asymptomatic patients with agranulocytosis before
The prevalence of agranulocytosis is about 0.5% but ranges from 0.5% to
176,204 The risk factors for agranulocytosis are unknown. There is no predilection
for either gender, and the reaction may be idiosyncratic or dose related. Some reports
suggest that patients older than 40 years or those taking high dosages of methimazole
(e.g., >40 mg/day) might be more susceptible than those on any dosage of PTU.
Although controversial, patients receiving low dosages of methimazole (e.g., <40
mg/day) might be at less risk than those receiving high or conventional dosages of
Agranulocytosis typically develops within the first 3 months of treatment, although
it can occur at any time and as late as 12 months after starting thioamide therapy.
delayed reaction is more common with methimazole therapy than with PTU. In 55
patients who developed agranulocytosis while taking thioamides, the duration of PTU
therapy (17.7 ± 9.7 days) was significantly shorter than for methimazole therapy
204 The mechanism of thioamide-induced agranulocytosis is
unknown. Both allergic- (idiosyncratic) and toxic-type (dose-related) reactions have
been suggested. An autoimmune reaction with circulating antineutrophil antibodies
and lymphocyte sensitization to antithyroid drugs has been demonstrated.
usually results from overwhelming infection.
If agranulocytosis is diagnosed, the drug should be discontinued, the patient
monitored for signs of infection, and antibiotics instituted if necessary. Granulocyte
colony-stimulating factors may shorten the recovery period.
recovers, granulocytes begin to reappear in the periphery within a few days to 3
weeks; a normal granulocyte count occurs shortly thereafter.
Although some cases of granulocytopenia have resolved with substitution or
continuation of thioamides, the risks of drug rechallenge clearly outweigh the
benefits, and other treatments
should be instituted. Changing to an alternative thioamide should also be avoided
because of possible cross-sensitivity between these agents.
In summary, all patients receiving thioamide therapy should be well educated
regarding the signs and symptoms of agranulocytosis. If these symptoms develop, they
should be advised to contact their physician or pharmacist. If they cannot reach their
own physician, patients should inform the emergency physician that they are taking
thioamides, and a WBC count with differential should be obtained. Routine
monitoring of a WBC and differential is not recommended until further studies justify
that it is indicated and cost-effective.
CASE 52-15, QUESTION 12: C.R.’s PTU is discontinued because she developed agranulocytosis and
C.R. should be in a euthyroid state at the time of surgery to avoid precipitation of
thyroid storm and morbidity. Generally, iodides (see Case 52-15, Question 2),
thioamides, or propranolol can be used.
173,192,200 The combination of iodides and
propranolol is more effective than either used alone. Propranolol used alone has
been associated with thyroid crisis postoperatively and may be less effective than
iodides in decreasing gland friability and vascularity.
Because C.R. received only 1 week of thioamide therapy, it is likely that her gland
still contains large stores of hormone; therefore, pretreatment is necessary.
In addition to the risks of anesthesia and surgery, postoperative complications
include hypoparathyroidism, adhesions, laryngeal nerve damage, bleeding, infection,
and poor wound healing. However, complications can be minimized if the surgery is
performed by experienced surgeons.
207 Complications are also higher if a total
rather than a subtotal thyroidectomy is performed, but there is a lower risk of
recurrent hyperthyroidism. Development of hypothyroidism, especially subclinical
hypothyroidism, is greatest during the first year after surgery, with an insidious rise
in incidence over the next 10 years. The incidence of permanent hypothyroidism
varies from 6% to 75% and is related inversely to the amount of remnant tissue left
207 Thyroid function tests should be monitored annually after surgery.
When total thyroidectomy is performed, postoperative L-thyroxine should be initiated
postoperative measurement of serum calcium and/or intact parathyroid hormone
REMISSION RATES WITH THIOAMIDES
usual size and has never decreased with therapy. Recent laboratory tests showed an FT4
thioamide therapy? Would the addition of T4
The high TSH level suggests that TSH stimulation caused by excessive
suppression of hormone synthesis by methimazole is contributing to the enlarging
thyroid gland. The easiest solution to this problem is to decrease the maintenance
dose of methimazole to 2.5 mg daily to normalize the TSH value and minimize gland
Long-term remission rates achieved with the thioamides are disappointing.
Remission rates within 6 years after discontinuing therapy average 50% (range,
175,176,195–197 although relapse rates are as high as 80%. The rate of
permanent remission is usually <25% if the follow-up period is long enough.
Why some patients remain in remission while others relapse once thioamides are
discontinued is unclear, although patients who remain euthyroid for >10 to 15 years
after discontinuing therapy probably do so because of disease progression to
Hashimoto’s thyroiditis rather than as a direct result of treatment.
the natural course of Graves’ hyperthyroidism might be eventual hypothyroidism
regardless of the treatment modality used. Several factors have a limited role in
predicting relapse and remission and have been used to guide therapy.
A longer duration of thioamide treatment (see Case 52-15, Question 7) improves
the remission rate by changing the basic underlying abnormality of Graves’
175,195–197 Numerous studies show that titers of antithyroid receptor (TSI) and
antimicrosomal antibodies fall during thioamide therapy but are unchanged during
therapy with placebo or β-blockers.
175,176,196,209 Patients with low or undetectable TSI
titers at the end of 12 to 24 months of thioamide therapy had a 45% chance of
remission compared to <10% chance of remission for those with higher titers within
1 to 5 years after completing therapy.
208–211 The best response was obtained in those
with smaller goiters, less severe disease, and nonsmokers. A higher thioamide dose
did not improve the remission rate but resulted in more toxicity, including
agranulocytosis, arthralgias, dermatitis, gastritis, and hepatotoxicity.
Certain clinical features have been associated with a greater chance of disease
remission and might help clinicians identify patients who deserve a longer thioamide
trial before changing to RAI or surgery. These clinical features include smaller
goiter, mild symptoms of short duration, a reduction in goiter size during treatment,
nonsmokers, absence of ophthalmopathy, and undetectable or low TSI levels.
Smokers should be advised to discontinue smoking to increase the chance of
remission (see Chapter 91, Tobacco Use and Dependence).
In a preliminary study, the addition of L-thyroxine to maintenance doses of
thioamides for 1 year, followed by an additional year of L-thyroxine alone,
significantly reduced the risk of relapse after stopping thioamides.
-methimazole combination experienced significant reductions in TSH receptor
antibody titers compared to those taking methimazole alone. At 3 years, the
combination-treated patients had a lower rate of recurrence after stopping therapy
(1.7%) than those receiving methimazole alone (recurrence rate, 34.7%).
Unfortunately, several prospective studies evaluating the addition of T4
have not validated these initial favorable results.
208,210,213,214 Support for this
therapeutic approach has waned, and the addition of T4
B.D.’s large goiter reduces her chance of remission with longer therapy. Although
thioamide therapy can be continued indefinitely if well tolerated, surgery or RAI
therapy should seriously be considered for B.D., who already has received
methimazole for >2 years. Alternative therapy is especially crucial if she plans to
become pregnant within the next few years (see Case 52-18).
hormone levels on routine blood tests. He is otherwise healthy and denies
J.C.’s laboratory findings of a suppressed TSH value below the limits of normal
and normal free thyroid hormone levels are consistent with subclinical
87–89 Other unlikely causes of a suppressed TSH in J.C.
include medications (e.g., metformin, bexarotene, glucocorticoids) (Table 52-1),
pituitary hypothyroidism, and non-thyroidal illness (see Case 52-1, Questions 1 and
10,60 A suppressed TSH may also be a normal finding in healthy elderly patients.
The dangers of SHyper are similar to those of overt hyperthyroidism and include
cardiac findings (e.g., atrial and ventricular premature beats, atrial f ibrillation [AF],
left ventricular hypertrophy, diastolic dysfunction), loss of bone mass, higher fracture
rates, especially in postmenopausal women, and if present, subtle symptoms of
In elderly patients, hyperthyroid symptoms, even if overtly
hyperthyroid, may be “apathetic” unapparent because of impaired sympathetic
nervous system responsiveness. A significant relationship between atrial f ibrillation
and degree of SHyper is clear, whereas an association with increased atherosclerotic
heart disease or mortality is weak.
158 The relative risk of AF in SHyper may be as
high as 5.2 and increased by older age, male gender, higher FT4
TSH suppression. In two cohorts followed for 10 to 13 years, the relative risk of
atrial f ibrillation ranged from 1.6 to 3.1, depending on the degree of TSH
158,215 The likelihood a patient with endogenous SHyper will progress to
overt hyperthyroidism is not clear. Patients may spontaneously revert to
euthyroidism, progress to hyperthyroidism or continue with SHyper. Individuals with
undetectable TSH concentrations appear most likely to progress, and overall the rate
of progression to overt disease is 1% to 5% annually.
with 7-year follow-up of SHyper importantly found 36% reverted back to normal
within 7 years, especially those with TSH levels between 0.1 and 0.4
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