Hyperthyroidism or thyrotoxicosis is the hypermetabolic syndrome that occurs
from excessive thyroid hormone production. Hyperthyroidism affects about 2% of
women and about 0.1% of men. The prevalence in older patients varies between
0.5% and 2.3% but accounts for 10% to 15% of all thyrotoxic patients.
The classic symptoms of hyperthyroidism are summarized in Table 52-5. The
typical symptoms are often absent in the older patient, producing a masked or
“apathetic” picture. Because of the atypical presentation in the older patient, occult
hyperthyroidism always must be considered, especially in patients with new or
worsening cardiac findings (e.g., atrial f ibrillation). Untreated hyperthyroidism can
progress to thyroid storm, a life-threatening form of hyperthyroidism characterized by
exaggerated symptoms of thyrotoxicosis and the acute onset of high fever. The
diagnosis of hyperthyroidism is confirmed by high serum concentrations of FT4 and
) or an undetectable TSH level. Positive thyroid antibodies confirm an
autoimmune origin for the hyperthyroidism (e.g., Graves’ disease).
Clinical and Laboratory Findings of Hyperthyroidism
Weight loss common, or weight gain caused by ↑ appetite
Diarrhea/frequent bowel movements
Nervousness, irritability, insomnia
Diffusely enlarged goiter, bruits, thrills
aThe fingernailseparates from its matrix, but only one or two nails are generally affected.
AST, aspartate aminotransferase; TgAb, thyroglobulin autoantibodies; DTRs, deep tendon reflexes; FT3
I, free triiodothyronine index; FT4
I, free thyroxine index; RAIU,
thyroid-stimulating hormone; TT3
Graves’ disease, an autoimmune disease, is the most common cause of
hyperthyroidism. Characteristics include diffuse goiter, ophthalmopathy
(exophthalmos), dermopathy (pretibial myxedema), and acropachy (thickening of
fingers or toes). The production of excessive thyroid hormone is attributed to a
circulating immunoglobulin G or thyroid receptor antibody (TRAb), which has a
TSH-like ability to stimulate hormone synthesis. The abnormal production of TRAb
by plasma cells (differentiated B lymphocytes) results from a deficiency of
suppressor T-cell lymphocytes. Other causes of hyperthyroidism, including
iatrogenic, are outlined in Table 52-6.
Both Graves’ disease and Hashimoto’s thyroiditis share similar clinical features
and can exist in the same gland: positive antibody titers, goiter with lymphocytic
infiltration of the gland, familial tendency, and predilection for women.
Thyrotoxicosis can precede the onset of Hashimoto’s hypothyroidism, and the end
result of Graves’ hyperthyroidism is often hypothyroidism.
Effective treatment options for hyperthyroidism include thioamides, radioiodine,
and surgery. Therapy selection is influenced by the etiology of the hyperthyroidism,
size of the goiter, presence of ophthalmopathy, coexisting conditions (e.g., angina,
pregnancy), patient age, patient preference, and physician bias. Radioactive iodine
(RAI) is preferred in older patients, those with coexisting cardiac disease,
ophthalmopathy, and a toxic multinodular goiter, whereas surgery is appropriate if
obstructive symptoms are present or concomitant malignancy is suspected. Pregnant
patients can be managed with thioamides or surgery in the second trimester; RAI is
The thioamides (e.g., methimazole, propylthiouracil) primarily prevent hormone
synthesis but do not affect existing stores of thyroid hormone. Therefore, hyperthyroid
symptoms will continue for 4 to 6 weeks after beginning thioamide therapy, and
initial treatment with β-blockers or iodides is often required for symptomatic relief.
Methimazole, given once daily, is considered the thioamide of choice versus
propylthiouracil (PTU), which requires 2 to 3 times daily dosing and has been
associated with severe and fatal hepatitis. PTU should be reserved for use during the
first trimester of pregnancy, in thyroid storm, and in those experiencing adverse
reactions to methimazole (other than agranulocytosis or hepatitis). The onset of action
of PTU is more rapid than methimazole in thyroid storm because PTU can also inhibit
the peripheral conversion of T4
. PTU is also preferred during the first trimester
of pregnancy because congenital defects have been reported with methimazole.
Although both drugs are secreted in breast milk, no adverse effects have been
reported in the exposed infants. The duration of treatment is empiric, and thioamides
typically are prescribed for 12 to 18 months in hopes of long-term spontaneous
remission once the drug is discontinued. Although thioamides maintain euthyroidism,
they do not change the natural course of the disease, and the likelihood of
spontaneous remission, once treatment is discontinued, is about 60%. The
combination of thioamide and T4
therapy to increase the likelihood of remission is
not effective nor recommended. Major adverse effects from thioamides include skin
rash, gastrointestinal (GI) complaints (e.g., nausea, upset stomach, and metallic
taste), agranulocytosis, and hepatitis. Cross-sensitivity between the thioamides is not
complete, and the alternative drug can be used if rash or GI complaints do not
resolve. This is not true for agranulocytosis and hepatitis, and the alternative agent is
Graves’ disease (toxic diffuse goiter); may be caused by polymorphisms in the TSH receptor
Toxic uninodular goiter (Plummer’s disease)
Nodular goiter with hyperthyroidism caused by exogenous iodine (Jod-Basedow)
Exogenous thyroid excess through self-administration (factitious hyperthyroidism)
mole with secretion of a thyroid-stimulating substance)
Nodular goiters, both multinodular and uninodular, are common thyroid problems
that occur in 4% to 5% of the adult population. The nodular goiter is usually found on
routine physical examination in asymptomatic and euthyroid patients. A cold nodule
is a “hypofunctioning” area of the thyroid that fails to collect radioiodine. Hot nodule
is a term used to describe a “hyperfunctioning” or iodine-concentrating area of the
thyroid. The hyperfunctioning autonomous nodule typically suppresses activity in the
remainder of the gland, but it does not produce clinical or chemical evidence of
hyperthyroidism and may remain unchanged for years. Some nodules may develop
into toxic goiters, causing overt symptoms of toxicosis. Most hot nodules are benign;
malignancies are rarely reported.
29 Treatment options include surgery, RAI, or
thyroid replacement therapy if hypothyroid. All goitrogens should be removed if
possible. L-Thyroxine suppression therapy is no longer recommended because the
dangers from supraphysiologic dosages of T4
(e.g., osteoporosis and the potential for
cardiac arrhythmias) outweigh the benefits. Nontoxic multinodular goiter is a
common finding in about 5% of the population.
In low-risk patients, long-standing
asymptomatic nodules that have not exhibited recent growth are likely to be benign
and can be followed or excised surgically for cosmetic reasons. If the patient
develops symptoms (swallowing or respiratory difficulty), surgery is the treatment of
choice. Observation with close follow-up is the preferred treatment option for most
Malignancy must be considered if there is recent growth in a “cold” single or
dominant nodule, a firm nodule clinically suspicious for cancer on a physical
examination, a history of thyroid irradiation, or a strong family history of medullary
thyroid carcinoma. Most cold nodules turn out to be benign adenomas rather than
cancers. The incidence of malignancy in a cold nodule varies between 10% and
30 A fine needle aspiration (FNA) of the thyroid nodule can document an
underlying malignancy. Surgery is indicated if malignancy is suspected or if any
obstructive or respiratory symptoms are present. After a total thyroidectomy for
thyroid cancer, RAI ablation is usually given to remove any remaining thyroid tissue.
A yearly evaluation for detection of recurrence of some thyroid cancers requires the
for 4 to 6 weeks, so that a repeat radioactive uptake and scan can
be completed. An elevated TSH level is also necessary to allow thyroglobulin
levels, a tumor marker, to rise if any malignant tissue is present. The administration
of recombinant human TSH may improve quality of life because comparable
elevations in TSH occur without stopping L-thyroxine therapy, reducing the duration
The principal laboratory tests recommended in the initial evaluation of thyroid
disorders are the TSH and the FT4
31–33 The relationship between laboratory
tests and thyroid disorders is summarized in Figure 52-2. The presence of thyroid
antibodies indicates an autoimmune thyroid etiology. Adjuncts to the previous tests
ultrasound, and FNA biopsy (Table 52-7).
Measurements of Free and Total Serum Hormone Levels
FREE THYROXINE, FREE THYROXINE INDEX, FREE
TRIIODOTHYRONINE, AND FREE TRIIODOTHYRONINE INDEX
) and free triiodothyronine (FT3
for the evaluation of hormone concentrations, especially when thyroid hormone–
binding abnormalities exist. The FT3
is most useful in hyperthyroidism but can be
normal or low in hypothyroidism. If a direct measure of the free hormone levels is
not available, the estimated free hormone indices (FT4
comparable information. However, these indices do not correct for changes observed
in patients with “euthyroid sick” non-thyroidal illnesses in whom TBG-binding
affinity is altered. In these circumstances, the FT4 and FT3 are preferable.
Figure 52-2 Evaluation of thyroid function tests. FT4
triiodothyronine; TSH, thyrotropin; TT4
Measurement of Circulating Hormone Levels
Direct measurement 0.8–1.4 ng/dL (10– No interference by Most accurate
of free thyroxine 18 pmol/L) alterations in TBG determination of FT4
(Table 52-1). Nonthyroidal illness (see
Tests of Thyroid Gland Function
Test of Hypothalamic–Pituitary–Thyroid Axis
TSH Pituitary TSH level 0.45–4.1
disorders detectable even after
<140% Confirms Graves’ disease;
<1.75 IU/L Confirms Graves’ disease;
Thyroglobulin Colloid protein of
aAt University of California laboratories.
TgAb, thyroglobulin auto antibodies; FT3
I, free thyroxine index; RAI, radioactive iodine; RAIU, radioactive iodine uptake; T3
, total thyroxine; T3RU, Triiodothyronine resin uptake.
TOTAL THYROXINE AND TOTAL TRIIODOTHYRONINE
) and total triiodothyronine (TT3
. Because the bound fraction is the major fraction
measured, situations that change the hormone’s affinity for TBG or the TBG level
will influence the results. For example, falsely elevated levels of TT4 and TT3 are
common in the euthyroid pregnant woman (see Case 52-3). In addition, the TT3
often low in older patients and in many acute and chronic non-thyroidal illnesses
because the peripheral conversion of T4
is decreased (see Case 52-1, Question
2 and Case 52-2). Therefore, careful interpretation of these tests is necessary in
situations that alter thyroid hormone binding, TBG levels, or T4
) is particularly helpful in detecting early relapse of
Graves’ disease and in confirming the diagnosis of hyperthyroidism despite normal
levels. Conversely, TT3 and FT3 are not good indicators of hypothyroidism
levels can be normal. Measurement of only the total hormone levels is
less reliable than either the free or estimated free hormone levels when alterations in
thyroid-binding globulin or non-thyroidal illnesses exist.
Tests of the Hypothalamic–Pituitary–Thyroid Axis
THYROID-STIMULATING HORMONE OR THYROTROPIN
The serum thyroid-stimulating hormone or thyrotropin (TSH) is the most sensitive
test to evaluate thyroid function.
31–33 TSH, secreted by the pituitary, is elevated in
early or subclinical hypothyroidism (when thyroid hormone levels appear normal)
and when thyroid hormone replacement therapy is inadequate. TSH can be abnormal
remains within the normal range because the TSH is specific for each
person’s physiologic set point. Polymorphisms in the TSH receptor contribute to this
27 Consequently, low normal free hormone levels can
stimulate the pituitary to synthesize increased amounts of TSH. TSH cannot
differentiate between primary hypothyroidism (thyroid failure), which is
characterized by elevated TSH levels, and secondary (pituitary or hypothalamus
failure) hypothyroidism where TSH levels may be low or normal. The TSH assay
can quantitate the upper and lower limits of normal, so that a suppressed TSH level
is highly suggestive of hyperthyroidism or exogenous thyroid overreplacement. Of
note, TSH is not entirely specific for thyroid disease because abnormal levels are
observed in euthyroid patients with non-thyroidal illnesses and in patients receiving
drugs that can interfere with TSH secretion. TSH secretion is increased at bedtime
and is affected by lack of sleep and exercise.
36 TSH secretion is suppressed
physiologically by dopamine, which antagonizes the stimulatory effects of TRH.
Therefore, both dopaminergic agonists and antagonists can alter TSH secretion (see
Case 52-4). Whether the upper limits of normal for TSH should be lowered to 2.5
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