Mild symptoms of hypothyroidism, including psychiatric and cognitive
abnormalities, are found in approximately 30% of patients with SH, but the average
TSH level usually exceeds 11 microunits/mL. Cardiac dysfunction, including
impaired left ventricular diastolic function at rest, systolic dysfunction with exercise,
atherosclerosis, CHF, and MI has been reported.
85,88,153–155 Data showing an increased
risk of coronary heart disease (CHD) are conflicting and influenced by the severity of
SH, study design, and length of follow-up. A meta-analysis noted a 1.6 times
156 a cross-sectional analysis noted an odds ratio of 2.2 only
in those with TSH levels of ≥10 microunits/mL, whereas a 20-year longitudinal
analysis found a significant risk (hazard ratio (HR) of 1.7) regardless of the degree of
157 However, a large prospective cohort study found no significant
association with atherosclerotic disease or cardiac mortality but observed an
increase in all-cause mortality at 10 years of follow-up.
from 11 large prospective cohorts with a median follow-up of 2.5 to 20 years
involving 3,450 subjects with subclinical hypothyroidism found an increased risk of
CHD (HR 1.89) and mortality (HR 1.5) but not total mortality only in those with TSH
level >10 microunits/mL after adjustment for traditional cardiovascular factors. No
increased CHD or CHD mortality was noted with more minimal TSH elevations.
Other atypical and nonspecific signs and symptoms reflecting dysfunction of any
part of the body may occur, primarily in the elderly. Failure to thrive, mental
confusion, weight loss with poor appetite, incontinence, depression, inability to
walk, carpal tunnel syndrome, deafness, ileus, anemia, hypercholesterolemia, and
hyponatremia have been reported.
Treatment of subclinical hypothyroidism with T4
is controversial because study
results are conflicting. Potential benefits of
treatment include (a) preventing progression to hypothyroidism, (b) improving the
lipid profile and reducing cardiac risks, and (c) reversing symptoms of
hypothyroidism. Patients with higher TSH levels (e.g., >10 microunits/mL), a history
of previously diagnosed thyroid disease, elevated lipid levels, or evidence of
positive thyroid antibodies gained the most benefit from L-thyroxine
85,88,152,155,160 L-Thyroxine significantly reduced total cholesterol by 7.9–15.8
mg/dL and low-density cholesterol concentrations by 10 mg/dL; serum HDL
cholesterol and triglyceride concentrations remain unchanged.
of elevated intraocular pressures, memory, mood, somatic complaints, and diastolic
dysfunction has also been reported after T4
Treatment of older patients requires an assessment of the risks versus benefits of
therapy. Thyroid therapy carries the risk of unmasking underlying cardiac disease in
older patients. Nevertheless, thyroid replacement appears reasonable in
asymptomatic patients with TSH levels >10 microunits/mL and especially those with
symptoms of mild hypothyroidism, dyslipidemia, laboratory abnormalities, or endorgan alterations.
87,88,152,154,160 Patients with mild subclinical hypothyroidism (TSH 6–
10 microunits/mL) may benefit from therapy with L-thyroxine 25 to 75 mcg/day when
there is evidence of cardiovascular risk (e.g., diastolic dysfunction, risk of
atherosclerotic disease, diabetes) or clinical indicators suggestive of hypothyroidism
88 There is no evidence supporting the treatment of mild
subclinical disease in patients over 80 years of age.
asymptomatic subclinical hypothyroidism and a TSH level <10 microunits/mL do not
warrant immediate therapy, but close follow-up is recommended.
Because M.P. is asymptomatic and has a TSH level <10 microunits/mL, it is
reasonable to delay therapy and recheck the TSH in a few months.
Hypopituitarism and Thyroxine Replacement with a
Normal Thyroid-Stimulating Hormone Level
3-month trial of L-thyroxine. How should the TSH level be interpreted? Is T4
therapy indicated based on her
Despite complaints that could be consistent with hypothyroidism (e.g., fatigue,
cold intolerance, dry skin, weight gain), the normal TSH level indicates that J.P. is
euthyroid. However, because a diagnosis of hypopituitarism (i.e., TSH level could
be normal or low) cannot be ruled out, an FT4
level should be obtained; a low level
would increase the likelihood of hypopituitarism. Some argue that hypopituitarism is
underdiagnosed and would advocate adding FT4
to the primary screening tests.
level is normal, indicating euthyroidism, then hypopituitarism is unlikely
symptoms and normal thyroid function tests was not more effective than placebo in
improving cognitive function or psychologic well-being despite changes in the TSH
In J.P., the T4 should be discontinued because there is no evidence of its efficacy
QUESTION 1: S.K., a 48-year-old woman, is admitted to the hospital for a possible MI. Her complaints
Laboratory data include the following results:
TSH, <0.5 microunits/mL (normal, 0.45–4.1)
RAIU at 24 hours, 80% (normal, 5%–35%)
INR, 4.8 (normal, 1; therapeutic, 2–3)
TPOAb, 200 IU/mL (normal, <0.8)
Alkaline phosphatase, 200 units/L
Alanine aminotransferase, 55 units/L
data are suggestive of hyperthyroidism in S.K.?
S.K. presents with many of the clinical and laboratory features
an increased metabolic state resulting from excessive T4
symptoms are consistent with Graves’ disease and include lid lag (lid falls behind
the movement of the eye and a narrow white rim of sclera becomes visible between
the upper lid and cornea, producing a “staring” appearance), ophthalmopathy
(protrusion of the eyeball), and decreased visual acuity. The thyroid bruit,
palpitations, exertional dyspnea, worsening CHF (JVD, bibasilar rales, edema,
hepatomegaly), diarrhea, irregular scant menses, nervousness, tremor, muscle
weakness, weight loss despite increased appetite, increased perspiration, and
flushing of the skin are consistent with a hypermetabolic state. Although sinus
tachycardia is the most common arrhythmia in hyperthyroidism, new-onset AF is the
presenting symptom in 5% to 20% of patients with hyperthyroidism, particularly in
165 Together with S.K.’s symptoms, a diagnosis of Graves’
disease is confirmed by an elevated FT4
level, an undetectable TSH level, an
increased RAIU, positive TPOAb, and a diffusely enlarged goiter. Her cardiac status
and other medical problems are aggravated by the hyperthyroidism. (Table 52-6 lists
the causes of hyperthyroidism.)
CASE 52-14, QUESTION 2: What factors contribute to S.K.’s hypoprothrombinemia? What effect could
this have on her subsequent drug treatment?
The hypoprothrombinemia and bleeding observed in S.K. are most likely related to
an exaggerated response to warfarin. This may be related to a decrease in the hepatic
metabolism of warfarin (secondary to hepatic congestion), but it is more likely that
S.K.’s findings are because of the combined effects of hyperthyroidism and warfarin
on vitamin K–dependent clotting factors.
Warfarin metabolism and the metabolism of vitamin K–dependent clotting factors can
be altered by thyroid status. Net circulating levels of vitamin K–dependent clotting
factors are generally not altered in hyperthyroid patients because both the synthesis
and catabolism of these clotting factors are increased. However, an enhanced
anticoagulant response occurs when the warfarin-induced decrease in clotting factor
synthesis is combined with the hyperthyroidism-induced increase in clotting factor
12,166 This may explain S.K.’s elevated INR, bruising, and history of
The opposite occurs in hypothyroidism, in which a decrease in both the
metabolism and synthesis of clotting factors occurs. In hypothyroid patients, the
response to oral anticoagulants is delayed because the clotting factors are eliminated
12,166 Therefore, hyperthyroid patients need less warfarin, whereas
hypothyroid patients require more warfarin to achieve the same
hypoprothrombinemic response. The anticoagulant response to warfarin should be
monitored carefully in patients with thyroid abnormalities, and the dosage adjusted as
Because S.K.’s hyperthyroidism will most likely be treated with a thioamide, caution
must be exercised. Treatment of hyperthyroid patients with thioamides, especially
PTU, has been associated with hypoprothrombinemia, thrombocytopenia, and
167 These drugs can depress the bone marrow and the synthesis
of clotting factors II, III, VII, IX, X, and XIII; vitamin K and prothrombin times may
remain depressed for up to 2 months after discontinuation of therapy. These effects
may be caused by a subclinical hepatic alteration in synthesis or hepatotoxicity (see
30,168–171 Symptoms occur 2 weeks to 18 months after
starting therapy. The bleeding is responsive to vitamin K or blood transfusions. (Also
s e e Case 52-15, Questions 3 and 4 for further discussion of treatment with
used to control her ventricular rate?
The AF of hyperthyroidism is often resistant to digitalis. When euthyroid patients
with AF were given digitalis before and after exogenous T3 administration, the daily
dose of digoxin required to maintain a ventricular rate of 70 was increased from 0.2
to 0.8 mg after T3 administration.
172 Higher dosages of digoxin without side effects
might be tolerated better by the hyperthyroid patient.
148,149,172 Nevertheless, the goal of
digoxin therapy should be a higher target heart rate (i.e., 100 beats/minute) than that
achieved with digoxin in the euthyroid patient with AF to minimize cardiac toxicity.
If additional rate control is required, β-blockers or calcium channel blockers (e.g.,
diltiazem or verapamil) can be added. Unless contraindicated by severe
bronchospasm, β-blockers rather than calcium channel blockers are preferred
because they are more effective in controlling the ventricular rate and are less likely
This apparent resistance to digitalis is attributed to intrinsic changes in myocardial
function, to an increased volume of distribution for digoxin, and to an increased
glomerular filtration of the glycoside.
148,149,172 Conversely, hypothyroid patients are
inordinately sensitive to the effects of digitalis and require smaller doses to achieve
a therapeutic response. Regardless of the mechanism, one should be aware that
higher-than-normal doses might be required in patients with thyrotoxicosis and that
the initial dosage should be reduced as the hyperthyroid state resolves.
S.K. should be maintained on warfarin because of a high prevalence of systemic
embolization in thyrotoxic patients with AF. Anticoagulation should be started when
the AF is first diagnosed and continued until S.K. is euthyroid and in NSR. This is
especially true for younger patients at low risk of bleeding with warfarin. The risks
versus benefits of anticoagulation should be weighed before therapy (see Chapter
16). Because an increased sensitivity to warfarin is observed, close monitoring is
warranted (see Case 52-14, Question 2). Cardioversion, either medical or electrical,
should not be attempted if she is still toxic because the success rate is low. If
cardioversion is to be used, it should not be attempted until the third or fourth month
T3 Thyrotoxicosis: Clinical Presentation
TSH, <0.01 microunits/mL (normal, 0.45–4.1)
TPOAb, 350 IU/mL (normal, <0.8)
Fasting blood glucose, 350 mg/dL
Assess these subjective and objective data.
C.R.’s laboratory findings of a positive TPOAb and elevated thyroid hormone
levels verify an autoimmune hyperthyroid state. However, the serum FT4
only slightly and is disproportionately low relative to the severity of her symptoms,
the undetectable TSH level, and her other laboratory findings. The low normal TT4
could be explained by displacement of T4
from TBG by aspirin (see Case 52-2). The
possibility of a variant type of hyperthyroidism known as T3
considered. The clinical features include signs and symptoms of thyrotoxicosis,
, an undetectable TSH level, and elevated T3
The latter occurs through preferential secretion and peripheral conversion of T4
level should be obtained to establish the diagnosis.
levels often precede elevation of T4
development of overt hyperthyroidism. T3
toxicosis probably represents an early
toxicosis and is useful for early diagnosis or as an early indicator
of relapse after discontinuation of thioamide therapy.
later ineffective? When are iodides indicated? What is their mechanism of action?
Iodides have several effects: They inhibit thyroid hormone release, they block
iodotyrosine and iodothyronine synthesis by blocking organification, and they
decrease the vascularity of the thyroid gland.
173 However, large doses may accentuate
hyperthyroidism because they provide a significant increase in available substrate for
hormone synthesis (see Case 52-24).
The inhibitory effect of exogenous iodides on the intrathyroidal organification of
iodides is known as the Wolff–Chaikoff effect. This is an inherent autoregulatory
function of the normal gland to prevent excessive hormone synthesis in the event of a
large iodide load. The Wolff–Chaikoff effect occurs when intrathyroidal
concentrations of iodides reach a critical level, and this is not overcome by TSH
stimulation. However, as illustrated by C.R., the gland can “escape” from this block
even with continued iodide use. The gland escapes by decreasing iodide transport or
by leaking iodide. Both mechanisms decrease the critical intrathyroidal iodide level,
thereby decreasing the block to organification. This effect is illustrated in C.R.
Therefore, iodides should not be used as primary therapy for Graves’ disease.
Conversely, some patients are responsive to iodide therapy, including (a) patients
who already have high intrathyroidal iodine stores (i.e., “hot” nodules, Graves’
disease); (b) patients with underlying defects in organic binding mechanisms (i.e.,
Hashimoto’s); (c) patients who develop drug-induced thyroid disorders (see Cases
52-23 and 52-24); and (d) patients with Graves’ disease made euthyroid with RAI or
surgery and who are receiving no thyroid replacement.
These patients are so sensitive that small doses of iodide can elicit the Wolff–
Chaikoff effect, resulting in either amelioration of hyperthyroid symptoms or
precipitation of hypothyroidism.
16,28,173 For this reason, patients with recurrent
hyperthyroidism after surgery or RAI can often be managed with iodides alone.
The most important pharmacologic effect of iodides is their ability to promptly
inhibit thyroid hormone release when dosages of 6 mg/day are given.
mechanism is unknown, but it is not related to the Wolff–Chaikoff effect, which may
take several weeks to manifest. Unlike the Wolff–Chaikoff effect, this effect can be
overcome partially by an increase in TSH secretion. Thus, the normal gland can
escape in 7 to 14 days because inhibition of thyroid hormone release stimulates a
reflex increase in TSH secretion. Because patients with hyperthyroidism experience
an improvement in symptoms within 2 to 7 days of initiation of therapy, inhibition of
hormone release must be the predominant mechanism of action for the iodides. This
rapid onset is the reason iodides are used in the treatment of thyroid storm and as an
ameliorative measure while awaiting the onset of the therapeutic effects of
Large doses of iodides are also used 2 weeks before thyroid surgery to increase
the firmness of the thyroid gland by decreasing its size, vascularity, and friability.
Iodides facilitate a smoother, less complicated surgery and reduce the risk of
postoperative complications by inducing a euthyroid state.
Stable iodine can be administered orally either as an unpleasant-tasting Lugol’s
solution (5% iodine and 10% potassium iodide), containing 8 mg/drop of iodide, or
as the more palatable saturated solution of potassium iodide (SSKI), containing 50
mg/drop of iodide. The minimum effective daily dose is 6 mg,
doses (e.g., 5–10 drops QID of SSKI) are often administered.
The advantages of iodide therapy are that it is simple, inexpensive, and relatively
nontoxic and involves no glandular destruction. Disadvantages include “escape,”
accentuation of thyrotoxicosis, allergic reactions, relapse after discontinuation of
treatment, and subsequent interference with RAI if used before therapy.
CASE 52-15, QUESTION 3: What are the advantages and disadvantages of the different treatment
modalities available for C.R.?
The three major treatment modalities for Graves’-related hyperthyroidism are the
thioamides, RAI, and surgery (Table 52-10).
In most cases, any of these three
modalities can be used, and there is controversy as to which is the most effective
therapy. Often the final decision is empiric, depending on the clinician’s available
resources and the patient’s desires. A review of treatment guidelines published by
the major endocrine organizations found that RAI is the most common treatment,
while surgery is the least common.
174 Patients who are older and those with cardiac
disease, concomitant ophthalmopathy, and hyperthyroidism caused by a toxic
multinodular goiter are treated best with RAI. Surgery is the preferred therapy for
pregnant women who are drug intolerant, when obstructive symptoms are present, or
The thioamides are the preferred treatment for children, pregnant women, and young
adults with uncomplicated Graves’ disease.
164,175,176 This is the only treatment that
leaves the thyroid gland intact and does not carry the added risk of permanent
hypothyroidism often associated with RAI or surgery.
Because the thyrotoxicosis of Graves’ disease might be self-limiting, thioamides
are used to control the symptoms until spontaneous remission occurs. Thioamides
should also be given before treatment with RAI or surgery to deplete the gland of
stored thyroid hormone, which prevents subsequent thyroid storm. Although
hyperthyroidism from toxic nodules will also respond to thioamides, more definitive
therapy (surgery or RAI) is needed because these conditions do not undergo
Disadvantages of thioamide therapy include the numerous tablets required, patient
adherence, possible drug toxicity, the long duration of treatment, and the low
remission rates after discontinuation of therapy (see Case 52-16).
The use of thioamides in C.R. has several potential drawbacks. Her relatively
large gland and severe disease make the prognosis for spontaneous remission
somewhat less favorable. A delay in the onset of thioamide’s effect may be expected
if intraglandular stores of thyroid have been increased by her prior iodide therapy.
Furthermore, her non-adherence and difficulty swallowing may necessitate another
means of treatment. Thioamides may also be prepared for administration by the rectal
Surgery is considered the treatment of choice
164,180–182 when (a) malignancy is
suspected; (b) esophageal obstruction, evidenced by difficulty swallowing, is
present; (c) respiratory difficulties are present; (d) contraindications to the use of
thioamides (e.g., allergy) or RAI (e.g., pregnancy) exist; (e) a large goiter that
regresses poorly on RAI or thioamide therapy is present; or (f) it is the patient’s
preference. Some argue that surgery is underused in the treatment of Graves’
In a prospective, randomized trial comparing the three treatment
modalities, surgery produced euthyroidism more quickly and was associated with a
lower relapse rate than either RAI or thioamides.
181 A meta-analysis of 35 studies
encompassing 7,241 patients with Graves’ disease found that thyroidectomy was
successful in 92% of patients with a low recurrence (7.2%) of hyperthyroidism.
C.R.’s minor difficulty in swallowing persists because of poor regression of goiter
size with drug therapy, then surgery is a reasonable alternative. If surgery is
contemplated, C.R. must be brought to surgery in a euthyroid state to prevent rapid
levels and subsequent thyroid storm (see Case 52-22,
Question 1). A total or near-total rather than a subtotal thyroidectomy is the
procedure of choice when performed by an experienced surgeon.
subtotal thyroidectomy theoretically avoids the predictable risk of hypothyroidism
from total thyroidectomy, the likelihood of recurrent hyperthyroidism increases in
proportion to the amount of residual thyroid tissue remaining.
thyrotoxicosis following a subtotal thyroidectomy should be treated with RAI
because the incidence of surgical complications increases with a second surgery.
fear of radiationinduced leukemia;
, thyroxine; TID, 3 times a day; TSI, thyroid receptor–stimulating or
thyroid-stimulating immunoglobulin; μCi, microcurie.
Surgical complication rates are low when the procedure is performed by a
competent surgeon and when the patient is adequately prepared for surgery. The
disadvantages of surgery are expense, hospitalization, hypothyroidism, the small risk
of postoperative complications, and the patient’s fear of surgery (see Case 52-15,
RAI, the most common treatment modality in the United States, is the preferred
treatment for (a) debilitated, cardiac, or older patients who are poor surgical
candidates; (b) patients who fail to respond to drug therapy or who experience
adverse drug reactions; and (c) patients who develop recurrent hyperthyroidism after
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