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The Cardiovascular System in Thyrotoxicosis

Irwin L. Klein
Sara Danzi
Almost two centuries ago, Caleb Parry reported on the association between thyrotoxicosis and
the cardiovascular system (1), and it is now clear that some of the most profound and
characteristic symptoms and signs of thyrotoxicosis are those relating to the cardiovascular
system (2). Understanding these effects has increased our understanding of the actions of
thyroid hormone (3,4). This chapter reviews the molecular, cellular, and organ responses to
thyrotoxicosis as it affects the cardiovascular system.
CARDIOVASCULAR HEMODYNAMICS
The changes in cardiovascular hemodynamics that occur in patients with thyrotoxicosis are
summarized in Table 31.1 (5,6). There are predictable decreases in systemic vascular
resistance and diastolic blood pressure, and increases in cardiac output, systolic blood
pressure, heart rate, left ventricular ejection fraction, cardiac contractility and mass, and blood
volume (6) (Fig. 31.1).

FIGURE 31.1. Actions of thyroid hormone on the heart and vascular system. (From Klein I.
Thyroid hormone and the cardiovascular system. Am J Med 1990;88:631, with permission.)
TABLE 31.1. CARDIOVASCULAR HEMODYNAMICS IN THYROTOXICOSIS
Change Comments
Systemic vascular ↓ 50%–70% lower
resistance
Cardiac output ↑ 200%–300% increase
Blood pressure
Systolic ↑ Especially in elderly patients
Diastolic ↓ Widened pulse pressure
Heart rate ↑ Most often sinus tachycardia; 2%–15% of patients have
atrial fibrillation
Cardiac contractility ↑ Increase in both systolic and diastolic function
Cardiac mass ↑ Hypertrophy from increased cardiac work
Blood volume ↑ Increased serum erythropoietin and sodium reabsorption
One of the earliest cardiovascular responses to thyroid hormone administration is a decrease
in systemic vascular resistance (7), which may decrease by as much as 50% to 70%. The
result is an increase in blood flow to the skin, muscles, kidneys, viscera, and heart (5). The
decrease in vascular resistance is specific for the systemic circulation. It may be caused by a
direct vascular action of thyroid hormone (7,8,9), or it may be due to stimulation of vascular
endothelial cells to release vasoactive substances such as nitric oxide (9,10). In patients with
thyrotoxicosis, β-adrenergic blockade blunts the thyroid hormone–mediated decrease in
systemic vascular resistance and the accompanying increase in cardiac output, and
administration of vasoconstrictor drugs increases systemic vascular resistance and
simultaneously decreases cardiac output (11).
Cardiac contractility is increased in virtually all patients with thyrotoxicosis (2,12,13).
Measures of systolic function, such as the rate of increase in ventricular pressure or velocity
of contraction, are uniformly increased (12). Measures of diastolic function, including the rate
of diastolic relaxation and compliance, also are increased (13).
Cardiac contraction results from the interdigitation of the two major contractile proteins, actin
and myosin, requires myosin-catalyzed hydrolysis of adenosine triphosphate (ATP) and has
an absolute requirement for calcium (4). One determinant of systolic contractility is the
maximum velocity of muscle fiber shortening, which correlates with the inherent ATPase
activity of the myosin molecule. There are two isoforms of cardiac myosin, α-myosin and β-
myosin; the ATPase activity of the heavy chains of α-myosin is greater than that of the heavy
chains of β-myosin. Each heavy chain is encoded by a different gene; the expression of the
gene for the heavy chain of α-myosin is stimulated by triiodothyronine (T3) in rodents
through an increase in gene transcription and posttranscriptional actions (14,15,16,17,18).
There are substantial species differences in the expression of cardiac myosin and the response
to T3. In humans, cardiac muscle obtained at autopsy contains predominantly β-myosin (3), as
did the cardiac muscle of a patient with thyrotoxicosis who died suddenly (19). Although
thyroxine (T4) therapy increased the content of mRNA for the heavy chain of α-myosin in a
patient with severe hypothyroidism (20), it is unlikely that thyroid hormone is a major
determinant of myosin isoforms or that substantial alterations in myosin gene expression
occur in humans with thyroid disease (3,21).
Calcium release from and reuptake into the sarcoplasmic reticulum of cardiac muscle
regulates the rate of ventricular contraction and relaxation. The gene for the cardiac-specific
calcium ATPase (SERCA2) that regulates the sequestration of calcium in the sarcoplasmic
reticulum during diastole is regulated by thyroid hormone (4,22). In addition, the expression
of the protein phospholamban, which is a negative regulator of calcium uptake by the
sarcoplasmic reticulum, is inhibited by T3 (22). Taken together, these observations could
account for the increase in calcium uptake in the sarcoplasmic reticulum and explain the
increased rate of development of systolic tension and diastolic relaxation in the heart of
patients with thyrotoxicosis (13,22).
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Increases in resting heart rate are characteristic of thyrotoxicosis (Table 31.2); more than 90%
of patients have resting tachycardia, and many have heart rates of 120 beats per minute or
higher (21,23,24). In addition to the increase in cardiac contractility, there also is an increase
in cardiac preload and a decrease in afterload, which combine to cause marked increases in
cardiac output both at rest and with exercise (25) (Fig. 31.1). Careful analysis of heart rate
regulation in patients with thyrotoxicosis revealed an increase in sympathetic tone and a
decrease in parasympathetic tone, the change from normal being greater in the former (26). In
addition, thyroid hormone may directly stimulate the sinus node pacemaker (21).
TABLE 31.2. PROMINENT SYMPTOMS AND SIGNS OF CARDIOVASCULAR
DYSFUNCTION IN PATIENTS WITH THYROTOXICOSIS
Palpitations
Exercise intolerance
Dyspnea on exertion
Angina pectoris
Orthopnea
Tachycardia
Atrial fibrillation
Hyperdynamic precordium
Widened pulse pressure
Cardiac flow murmurs
Pedal edema
Third heart sound (S3)
Serum erythropoietin concentrations are increased in patients with thyrotoxicosis, presumably
in response to the need to increase peripheral oxygen delivery. Renal sodium reabsorption is
increased as a result of activation of the renin–angiotensin–aldosterone system and
increases in renal perfusion and renal Na+,K+-ATPase activity. These changes may explain the
increases in total blood volume, plasma volume, and erythrocyte mass reported in patients
with thyrotoxicosis (3,6).
CARDIOVASCULAR PATHOPHYSIOLOGY
Cardiac Effects
T3 regulates the transcription and translation of multiple cardiac genes, and it (and perhaps
also T4) may have extranuclear actions on cardiac muscle as well (4,15,27) (Table 31.3). T3
regulates gene transcription by binding to specific nuclear receptors, and the complexes bind
to specific DNA sequences [thyroid hormone–response elements (TREs)] located on target
genes in cardiac myocytes (28,29) (Fig. 31.2). The two isoforms of the T3 nuclear receptors
(α1, and β) that bind T3, and the α2 form, that does not bind T3 have been identified in left
ventricular muscle and in isolated cultured cardiac myocytes (see Chapter 8) (16). T3 has
direct effects on the rate of gene transcription in isolated cardiac myocytes (14,15). These
effects occur within 30 minutes and result in an increase in myocyte RNA content and protein
synthesis (4,14). T3 also increases the rate of translation and stability of messenger RNA
(mRNA) in these cells (15,18).
FIGURE 31.2. Cellular mechanisms of action of triiodothyronine (T3) on cardiac myocytes.
T3 binds to T3 nuclear receptors, and the T3 receptor complexes then bind to thyroid hormone
response elements of specific myocyte genes, including the genes for α-myosin heavy chains,
Ca2+-ATPase, phospholamban, sarcoplasmic reticulum, β-adrenergic receptors, adenylyl
cyclase, guanine-nucleotide-binding proteins, Na+/Ca2+ exchangers, Na+/K+-ATPase, and
voltage-gated potassium channels. T3 also has nonnuclear actions on ion channels in the cell
membrane. (Reproduced from Klein I, Ojamaa K. Thyroid hormone and the cardiovascular
system. N Engl J Med 2001;344:501, with permission.)
TABLE 31.3. EFFECTS OF TRIIODOTHYRONINE ON CARDIAC GENE
EXPRESSION
Gene Effec Comment
t
Myosin heavy chain Effect mainly in small animals
content
α ↑ Fast myosin
β ↓ Slow myosin
Sarcoplasmic Ca- ↑ May determine ventricular diastolic function through calcium
ATPase reticulum regulation
Phospholamban ↓ Acts in concert with sarcoplasmic reticulum Ca-ATPase
Na+, K+-ATPase ↑ Tissue- and isoform-specific regulation of transmembrane ion
flux
Atrial natriuretic ↑ Reduces renal salt and water reabsorption, and lowers blood
hormone pressure
β-adrenergic receptor ↑ Tissue-specific, may in part explain the change in adrenergic
tone characteristic of thyrotoxicosis through changes in
adenylyl cyclase activity
Adenylyl cyclase ↓ Isoform-specific regulation
catalytic subunit
Gs proteina ↑
Gi proteinb ↓
Potassium channel ↑ Rapidly responsive, voltage-gated potassium channel
(Kv1.5)
a
The guanine nucleotide-binding protein that mediates stimulation of adenylyl cyclase
activity.
b
The guanine nucleotide-binding protein that mediates inhibition of adenylyl cyclase activity.
The different isoforms of the T3 nuclear receptors present in cardiac myocytes may mediate
the different genomic actions of T3 in both the atria and ventricles (16). Indeed, some of the
functional and chamber-specific effects of thyroid hormone on the heart may be mediated by
a specific receptor isoform. Studies of mice with deletions or mutations of the receptors
suggest that the α1 form of the receptor mediates T3 stimulation of heart rate (30), and that
the β form is less important in so far as the actions of T3 in the heart are concerned (31).
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Evidence for indirect effects of thyroid hormone on the heart mediated by changes in
cardiovascular hemodynamics comes from studies of the cardiac hypertrophic (growth)
response to thyrotoxicosis. In humans and animals, chronic thyrotoxicosis causes variable
degrees of cardiac hypertrophy (3,23). If this hypertrophy was caused by a direct effect of
thyroid hormone on cardiac protein synthesis, it should not be affected by β-adrenergic
blockade. However, both propranolol and bisoprolol block or reverse thyroid
hormone–induced cardiac hypertrophy (32). These results suggest that increased cardiac
work is the major mediator of the cardiac growth response in thyrotoxicosis. Further
confirmation comes from experiments with heterotopically transplanted hearts in which the
heart was exposed to high serum thyroid hormone concentrations without an accompanying
increase in cardiac work (18,33). Under these circumstances, cardiac hypertrophy did not
occur, but cardiac gene expression and heart rate increased (18).
In addition to its genomic actions, T3 has nongenomic or nonnuclear actions on the heart.
These actions, because of their rapid time course and lack of associated changes in mRNA or
protein synthesis, imply that T3 acts at the plasma membrane, sarcoplasmic reticulum, or
mitochondria (27,34). In the plasma membrane of cardiac myocytes, T3, in a concentration of
10 mol/L, increases Na+ ion currents by opening Na+ ion channels. Additional plasma
membrane actions that may be directly regulated by T3 include shortening the duration of
action potentials by an effect on voltage-dependent potassium channels and increasing
calcium transport in the sarcoplasmic reticulum, nucleotide translocase activity, magnesium
flux, and oxidative phosphorylation in mitochondria (27). These nongenomic actions of T3
may explain, at least in part, the increases in cardiac contractility and cardiac output and
decreases in systemic vascular resistance that occur within a few hours in patients given high
doses of T3 intravenously after cardiopulmonary bypass surgery (7).
Peripheral Circulatory Effects
In patients with thyrotoxicosis, systemic vascular resistance is reduced from normal values
(~1,700 dynes/sec/cm3) to values as low as 500 to 700 dynes/sec/cm3 (5,6). In animals given
T3, the decrease is rapid, occurring before changes in heart rate or cardiac contractility. The
decrease in resistance is especially prominent in skeletal muscle, and it also occurs in other
organs, including skin and viscera (5,8,11). As systemic vascular resistance declines, so does
blood pressure, which in turn causes a reflex increase in heart rate, stroke volume, and cardiac
output (Fig. 31.1). The reflex nature of these latter changes is supported by the observation
that prevention of the decline in systemic vascular resistance with the β-adrenergic agonist
propranolol mitigates or prevents some of the inotropic and chronotropic responses to T3 (11).
As noted above, T3 reduces peripheral vascular resistance through two separate mechanisms
(8,35). One is due to a direct action of T3 on arterial smooth muscle tone, as indicated by the
ability of T3 to cause relaxation of cultured vascular smooth muscle cells (8). Second, T3
stimulates the synthesis, secretion, or action of vasodilators by endothelial cells (11). In rats,
synthesis of nitric oxide from L-arginine by nitric oxide synthase in endothelium is stimulated
by thyroid hormone (35), and in patients with thyrotoxicosis, increased nitric oxide
production contributes to the decreased vascular resistance and increased vascular reactivity
(36). In addition, the vascular response to acetylcholine, another endothelium-dependent
vasodilator, is increased in patients with thyrotoxicosis. In contrast, the vascular response to
nitroprusside, an endothelium-independent vasodilator, is not increased, indicating that the
endothelium is a specific target for thyroid hormone in mediating peripheral vascular effects
(36).
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Thyroid hormone increases the synthesis and secretion of renin and angiotensinogen, the
formation of angiotensin II, and the secretion of aldosterone (6,33). This activation of the
renin–angiotensin–aldosterone system contributes to the increases in renal sodium
absorption and blood volume that occur in thyrotoxicosis.
Thyrotoxicosis can cause hypertension (33,37). This is primarily systolic hypertension, with
decreased or normal diastolic pressure and an increase in pulse pressure. The increase in
systolic pressure is in part due to decreased arterial compliance, which in turn appears to be
the result of the tachycardia that is so common in patients with thyrotoxicosis (25). The
prevalence of this finding is estimated at 25% in patients between 30 and 65 years of age
(6,37).
CLINICAL MANIFESTATIONS
The cardiovascular symptoms and signs of thyrotoxicosis are some of the most characteristic
and disabling manifestations of the disorder (2,38) (Table 31.2). Many of these symptoms and
signs mimic those that occur in states of increased β-adrenergic activity, such as
pheochromocytoma (39). The overlap of symptoms and signs of thyrotoxicosis and those of
hyperadrenergic states suggested that catecholamine metabolism might be altered in
thyrotoxicosis (4,39), but in fact plasma norepinephrine and epinephrine concentrations are
normal or low, and urinary excretion of catecholamine metabolites (including
normetanephrine, metanephrine, and vanillylmandelic acid) is normal (see Chapter 38) (40).
Nearly all patients have tachycardia, and most have palpitations. The latter symptom refers to
a sensation of forceful beating of the heart (2,23,38), and it may be caused by sinus
tachycardia or atrial arrhythmias (3,26,41), increased cardiac contractility, or both. Patients
often note that their heart rate increases excessively during exercise and declines slowly after
exercise (38). The heart rate is rapid both during the day and during sleep, and the normal
diurnal variation in heart rate is blunted (2,4,26). This change may be due to decreased
parasympathetic tone, which is also suggested
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by the loss of normal heart rate variability as measured by changes in the R-R interval on the
electrocardiogram (26).
Other common cardiovascular symptoms include exercise intolerance and dyspnea on
exertion (13). These symptoms are probably caused by a less-than-normal increase in cardiac
output (25) and respiratory muscle weakness (2,42). Treatment of patients with thyrotoxicosis
with β-adrenergic antagonist drugs results in improvement in both muscle strength and
exercise performance (38,40,42).
In elderly patients, the cardiac manifestations of thyrotoxicosis may be limited to resting
tachycardia (23,41), and other symptoms may be absent, possibly due to a relative paucity of
adrenergic activity (38,39,43). With the onset of atrial fibrillation (44,45), the extent of
cardiovascular manifestations increases, and rate-related heart failure may occur (2,3).
Rarely, young patients with thyrotoxicosis may have chest pain similar in almost all respects
to angina pectoris (2,3,46). The mechanism is either relative myocardial ischemia resulting
from a mismatch between cardiac oxygen supply and demand (47), or coronary artery spasm
(46). Anginal pain that begins after the onset of thyrotoxicosis usually disappears after
antithyroid treatment is begun. In older patients, the increased myocardial oxygen demand
due to thyrotoxicosis may unmask previously unsuspected coronary artery disease (2,21,47).
The clinical importance of these cardiovascular effects of thyrotoxicosis is evident from
recent studies that confirmed the suspicion that the mortality of patients with thyrotoxicosis is
increased, primarily as a result of cardiovascular disease (48,49). In particular, atrial
fibrillation is a poor prognostic feature, especially in older patients, as is the combination of
thyrotoxicosis and valvular or hypertensive heart disease (see Chapter 77).
Physical Examination
Tachycardia is perhaps the most common of all abnormal findings on physical examination of
patients with thyrotoxicosis. Not only is the measured heart rate fast, but often the pulse in the
larger arteries is bounding due to widened pulse pressure with high systolic and low diastolic
blood pressures (5,6) (Table 31.2). Mean blood pressure is usually normal or slightly low.
Older patients may have an exaggerated increase in systolic blood pressure because of the loss
of elasticity of the larger (capacitance) arteries (25); their mean blood pressure may also be
high (6,43).
Findings on physical examination suggesting an increase in cardiac contractility and cardiac
output include a rapid increase in the carotid upstroke, a sharp and easily audible first heart
sound, a hyperdynamic precordium, and a prominent apical impulse. Auscultation may reveal
a systolic murmur caused by rapid flow of blood through the aortic outflow tract. Systolic
murmurs due to regurgitant flow across the mitral valve may arise from left ventricular
dilatation or mitral valve prolapse. A systolic “scratch” is occasionally heard in the
pulmonic area (second left intercostal space), corresponding to contact between the pleural
and pericardial surfaces during cardiac contraction. This murmur may also be due to an
increase in pulmonary artery pressure (6,33,50). These clinical findings are confirmed by
noninvasive cardiac diagnostic studies in patients with thyrotoxicosis, including radionuclide
angiography to measure left ventricular ejection fraction and Doppler echocardiography to
assess cardiac systolic and diastolic performance (13,47).
The occurrence of pedal edema or pleural effusions signifies the presence of fluid overload.
Rarely, as noted below, symptoms and signs of true congestive heart failure, including a
decrease in left ventricular contractility, the presence of a third heart sound (S3), and
paroxysmal nocturnal dyspnea, may be present (2,3,19,21).
Cardiac Rhythm Disturbances
Sinus tachycardia at rest, during sleep, and during exercise is the most consistent rhythm
disturbance in patients with thyrotoxicosis (24,25,26,51). The reported prevalence rates for
supraventricular arrhythmias (supraventricular tachycardia or atrial fibrillation) in patients
with thyrotoxicosis vary greatly (Table 31.2). Some studies report a very low prevalence (<
1% to 2%) of these arrhythmias, perhaps reflecting early diagnosis; in other studies from 5%
to 15% of patients had atrial fibrillation (2,44,45). Although most patients with thyrotoxicosis
who have atrial fibrillation are elderly, it can occur in younger patients (52). The ventricular
rate in atrial fibrillation is often rapid, as a result of an increased rate of conduction of
electrical impulse through the atrioventricular node. Most patients with atrial fibrillation have
the arrhythmia for a relatively short time (< 4 to 8 weeks) before the diagnosis of
thyrotoxicosis is made. In the absence of evidence for chronicity, spontaneous reversion to
sinus rhythm within 8 to 12 weeks after the initiation of antithyroid treatment is the rule (44).
Reversion to sinus rhythm during or after treatment of the thyrotoxicosis is less common in
elderly patients with chronic atrial fibrillation or patients who have underlying coronary or
other heart disease, and in these patients electrical cardioversion may be needed to restore
sinus rhythm (44). Patients restored to sinus rhythm by electrical cardioversion or drug
therapy are more likely to remain in sinus rhythm if treated with disopyramide (53,54).
The development of atrial fibrillation poses the potential for systemic embolization, including
stroke. However, the risk for embolism is low, and its occurrence is limited largely to older
patients with coexisting heart disease (55). The value of anticoagulation is controversial; it is
discussed in more detail below.
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Atrial flutter and other supraventricular tachyarrhythmias (including paroxysmal atrial


tachycardia) occur but are uncommon in patients with thyrotoxicosis. Ventricular premature
contractions and ventricular fibrillation are extremely rare (21,40,56,57), and their occurrence
suggests the presence of hypokalaemic periodic paralysis (see Chapter 41) (58).
Electrocardiographic changes include not only disturbances in rhythm but also nonspecific ST
segment and T-wave abnormalities. The P-R interval is often short, secondary to the increased
rate of conduction through the atrioventricular node. Some patients have electrocardiographic
signs of left ventricular hypertrophy, which disappear during antithyroid therapy or β-
adrenergic blockade (59). Patients with angina-like symptoms may have ST-segment
elevations, suggesting myocardial ischemia (46).
Congestive Heart Failure
Some patients with thyrotoxicosis have heart failure. Most are elderly, and therefore likely to
have underlying heart disease, or they have atrial fibrillation (41). In the absence of atrial
fibrillation, heart failure is rare (3,21). Hypertension, valvular heart disease, or coronary artery
disease predisposes patients to cardiac contractile dysfunction when the workload and oxygen
consumption increase, as characteristically occurs in thyrotoxicosis (3,25,47). Nonetheless,
heart failure—or at least fluid overload—can occur in patients, even young patients, with
thyrotoxicosis with no known heart disease and in the absence of atrial fibrillation. This
finding has led to the suggestion that thyrotoxicosis can cause cardiomyopathy. More likely,
plasma volume and cardiac preload are increased at the same time that cardiac contractility is
increased, giving rise to circulatory congestion (3,25).
Excluding patients with atrial fibrillation and rapid ventricular rates, a comparison of patients
with thyrotoxicosis who did or did not have heart failure revealed two important differences.
Patients with heart failure had higher levels of systemic vascular resistance and a
disproportionate increase in systemic vascular resistance with exercise (5). Heart failure in
patients with thyrotoxicosis who do not have underlying heart disease usually is considered to
be “high output” (21). That a high cardiac output per se could lead to cardiac failure is
controversial, and high-output heart failure may not be heart failure but rather circulatory
congestion caused by fluid retention (5,6). Support for this possibility comes from the finding
of increased blood volume with increased venous filling pressures and peripheral edema (21)
and the prompt clinical response to diuretic treatment (33).
In patients with thyrotoxicosis, cardiac output does not increase to the same extent as it does
in normal subjects in response to exercise, stress (infection), surgery, or pregnancy (3,21,25).
As a result, atrial filling pressures increase, leading to pulmonary and peripheral edema (a
situation inevitably worsened by atrial fibrillation because it impairs atrial and ventricular
filling) (47). This limitation in cardiac output is a result of a less than expected increase in left
ventricular contractility during exercise (60), which improves after antithyroid treatment,
suggesting the presence of a reversible thyrotoxic cardiomyopathy. An alternative explanation
is that resting systemic vascular resistance is already maximally lowered and therefore cannot
decline further with exercise (5,6). In the absence of such a decline, left ventricular afterload
and contractility may not increase, and therefore cardiac output would not increase. These
observations further reinforce the importance of changes in systemic vascular resistance,
blood volume, and loading conditions as determinants of cardiovascular function in
thyrotoxicosis (3,25).
Perhaps the most compelling explanation of impaired left ventricular function (decreased
ejection fraction, decreased diastolic compliance, and an S3 on physical examination) in
patients with thyrotoxicosis is the observation that persistent tachyarrhythmias per se decrease
left ventricular contractile function, causing rate-related heart failure (33,61). Sustained
tachycardia in general decreases ventricular systolic and diastolic function, which resolves
when the heart rate slows (62), and there is no reason to doubt that sustained sinus tachycardia
(or atrial fibrillation) in patients with thyrotoxicosis has the same effect (2,24,63). Additional
support for the importance of this mechanism of cardiac dysfunction in patients with
thyrotoxicosis is the rapid improvement in ventricular function that occurs when the heart rate
is slowed by administration of a β-adrenergic antagonist drug (40). The finding that heart
failure improves with antithyroid treatment obscures the fact that it is the heart rate that is
simultaneously controlled and may have been the primary cause for the heart failure
(21,41,61).
Subclinical Thyrotoxicosis
Subclinical thyrotoxicosis is defined as a low serum thyrotropin (TSH) concentration and
normal serum free T4 and T3 concentrations. Many of these patients have no symptoms or
signs of thyrotoxicosis, but some have resting tachycardia or transient episodes of atrial
fibrillation that are unrecognized (23), and they may be at risk for the cardiovascular
manifestations associated with overt thyrotoxicosis (see Chapter 79) (33,64,65). For example,
among older people, the 10-year risk for atrial fibrillation in those with serum TSH
concentrations of less than or equal to 1 mU/L was three times higher than in those with
normal serum TSH concentrations (45). In a similar study, a low serum TSH concentration in
patients 61 years of age and older was associated with increased all-cause and cardiovascular
mortality (see Chapter 77) (65). Furthermore, young and middle-aged patients with
subclinical thyrotoxicosis
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have some cardiac dysfunction, in that they have higher average heart rates, increased left
ventricular mass, increased systolic contractility, and impaired diastolic function, as compared
with age-matched normal subjects (62). These changes improve in response to antithyroid
therapy, strongly suggesting that the changes are caused by the small increases in serum T4
and T3 concentrations within the normal reference range that define subclinical thyrotoxicosis
(66,67,68).
TREATMENT
Patients with thyrotoxicosis should be treated to reverse the hemodynamic changes that
accompany thyrotoxicosis without impairing the ability of the heart to meet the needs of
peripheral tissues for oxygen and substrates (2,3,47) (Table 31.4). Ultimately this requires
antithyroid treatment of some type (67). However, the available treatments do not rapidly
reduce thyroid hormone secretion, and therefore treatments that can rapidly reduce the actions
of thyroid hormone often are indicated in patients with thyrotoxicosis who have
cardiovascular dysfunction (40,69).
TABLE 31.4. TREATMENTS FOR CARDIOVASCULAR MANIFESTATIONS OF
THYROTOXICOSIS
Acute treatment of tachycardia or exercise-related symptoms
β-adrenergic antagonist drugs
Calcium channel–blocking drugs (when β-blockade is contraindicated)
Acute treatment of heart failure
β-adrenergic antagonist drugs: indicated for rate-related heart failure and control of
ventricular response in atrial fibrillation
Diuretic drugs
Digoxin: greater than usual loading and maintenance dosage may be needed
Anticoagulation: consider for patient with chronic atrial fibrillation
Chronic treatment of hyperthyroidism
Radioiodine
Antithyroid drug therapy
Because of the importance of reduction in heart rate, initial therapy of patients with
thyrotoxicosis with or without underlying heart disease is best accomplished by
administration of a β-adrenergic receptor antagonist drug (40). Propranolol, a nonselective β-
adrenergic antagonist drug, has been used most often for this purpose; usually, it is given in
divided doses of 80 to 240 mg per day (13,42). Selective β-adrenergic antagonist drugs like
atenolol or metoprolol are equally effective. Propranolol in low doses (1 to 2 mg) can be
given by slow intravenous infusion in more acutely ill patients, provided that they are
monitored continuously. The goal is to slow the heart rate, which should decrease not only
palpitations but also any signs of cardiac decompensation, maintain blood pressure, and
improve some of the noncardiac symptoms of thyrotoxicosis (38,42). Although heart failure
was previously considered a contraindication to administration of β-adrenergic antagonist
drugs, it is not in patients with thyrotoxicosis because of the benefit of heart rate control in
reversing left ventricular dysfunction. The β-adrenergic antagonist drug should be continued,
in decreasing doses, until the patient is euthyroid (40,67).
Calcium-channel blockers, when administered orally, also slow the heart rate in patients with
thyrotoxicosis (24). Acute administration of these drugs, however, may have the undesired
effect of further lowering systemic vascular resistance, leading to hemodynamic instability,
which in turn requires treatment by volume expansion. When β-adrenergic antagonist drugs
are contraindicated, a calcium-channel blocker can be given to control atrial fibrillation or
other supraventricular arrhythmias, but it should be given cautiously to avoid hypotension or
negative inotropic actions (3,21).
Patients with symptoms and signs of heart failure, including peripheral (or pulmonary) edema,
should be treated with furosemide. Diuresis is as effective as it is with other forms of
congestive heart failure. Volume contraction, however, should be avoided because it can
impair cardiac filling and lower cardiac output. In addition to diuresis with furosemide,
digoxin can be beneficial in both controlling the symptoms and signs of heart failure and
slowing the ventricular rate in patients with atrial fibrillation. The clearance of digoxin is
increased, and cardiac sensitivity to digoxin may be decreased, in patients with thyrotoxicosis,
and therefore higher than average doses may be needed (33).
Treatment of thyrotoxicosis is discussed in detail in Chapter 45. Among the available
treatments, radioiodine seems particularly appropriate for patients with many cardiovascular
manifestations of thyrotoxicosis. Among 356 patients with cardiovascular manifestations of
thyrotoxicosis, including atrial fibrillation, angina pectoris, or heart failure, more than 90%
had improvement in their symptoms and signs after treatment with radioactive iodine (41). In
one study, mortality from cardiovascular disease was increased in patients treated with
radioiodine, as compared with the population at large, but the increase was probably due to
the presence of severe thyrotoxicosis rather than to the radioiodine therapy (48).
The role of anticoagulation in patients with thyrotoxicosis who have atrial fibrillation is
controversial. A retrospective study supporting the use of anticoagulation involved a
relatively small number of patients (70), and was not confirmed by other, larger retrospective
studies (44,55). It appears that age, rather than the presence of atrial fibrillation, is the major
risk factor for systemic embolization in these patients (56,71). Although anticoagulation
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clearly lowers the incidence of embolization in patients with atrial fibrillation in general (72),
it has risks. Furthermore, in many patients with thyrotoxicosis who have new-onset atrial
fibrillation, the rhythm reverts to sinus rhythm soon after antithyroid treatment is initiated
(44). Therefore, anticoagulation is not universally indicated; low-dose aspirin is a reasonable
alternative. Anticoagulation should be considered, however, in patients with thyrotoxicosis
who have underlying cardiac disease or in whom the atrial fibrillation persists, subject to the
age and other guidelines applicable to any patient with atrial fibrillation (72). Patients with
thyrotoxicosis tend to be more sensitive to warfarin than those who are euthyroid (see Chapter
35).
SELECTED CLINICAL SITUATIONS
Treatment with Amiodarone
Amiodarone is an iodine-rich antiarrhythmic drug that is effective in patients with ventricular
and atrial tachyarrhythmias. It may induce both hypothyroidism and thyrotoxicosis (see
section Effect of Excess Iodide in Chapter 11) (73), and therefore thyroid function should be
assessed regularly in patients receiving amiodarone, and for at least 6 months after it is
stopped, because it is excreted very slowly. The prevalence of amiodarone–induced
thyrotoxicosis is as high as 10% (73,74). There are two types of amiodarone–induced
thyrotoxicosis. Type 1 occurs primarily in patients who have preexisting thyroid disease,
mostly mulinodular goiter, and is thought to be due to iodine excess, and type 2 is a form of
thyroiditis (73,74). Patients with type 1 amiodarone–induced thyrotoxicosis have usually
been treated with an antithyroid drug, and sometimes also potassium perchlorate (to block
thyroid uptake of iodine) or surgery, and those with type 2 amiodarone–induced
thyrotoxicosis with a glucocorticoid (73,74,75,76). In fact, in many patients the thyrotoxicosis
cannot be neatly categorized as type 1 or 2, and initial therapy should probably consist of an
antithyroid drug and a glucocorticoid (33,73,74,75). Cessation of amiodarone has little
immediate effect, even if acceptable from the perspective of the patient's cardiac disorder,
because the drug is stored in adipose tissue and excreted very slowly (months) (74).
Pregnancy
The cardiovascular changes of pregnancy, which are similar to those of thyrotoxicosis, result
from the need to deliver oxygen and substrates to the enlarging placenta, which is perfused
through a low-resistance vascular bed, and the developing fetus (77). In pregnant women with
thyrotoxicosis the hemodynamic effects of the two conditions are additive. In these women,
appropriate antithyroid treatment usually prevents any untoward burden on the heart
(40,67,77). Peripheral edema, marked tachycardia, or symptoms of cardiac decompensation
should be treated in the same way in pregnant women with thyrotoxicosis as in other patients.
β-adrenergic antagonist drugs should be given cautiously because they may cause fetal
growth retardation when given in early pregnancy and prolong labor and delivery when given
nearer to or at term (40,77).
Right Heart Failure and Pulmonary Hypertension
Right heart failure often accompanies left heart failure, but predominantly right-sided heart
failure with preserved left ventricular function is rare in patients with thyrotoxicosis (78).
However, pulmonary hypertension may not be rare in patients with thyrotoxicosis; in one
study the prevalence was 41% (50), indicating that excess thyroid hormone does not lower
pulmonary vascular resistance, in contrast to its effects on systemic vascular resistance.
Primary pulmonary hypertension is a rare, often fatal disease of unknown etiology that
primarily affects young women. Among these patients, the frequency of Graves' disease (and
chronic autoimmune thyroiditis) is increased (79).

The Blood in Thyrotoxicosis


Stephanie A. Fish
Susan J. Mandel
Thyrotoxicosis affects hematopoiesis in several ways, although clinically important
abnormalities are rare. This chapter discusses the effects of thyrotoxicosis on erythrocytes,
leukocytes, platelets, and coagulation factors.
ERYTHROCYTES
Thyrotoxicosis stimulates erythropoiesis both indirectly and directly. Serum erythropoietin
concentrations are higher in thyrotoxic patients as compared with normal subjects, probably
as a result of the increase in metabolic activity and the concomitant increase in need for
peripheral oxygen delivery (1,2,3,4). Thyroid hormone may also stimulate mononuclear cells
to release tissue-specific erythroid stimulatory factors (5) and directly stimulate the formation
of erythroid progenitor cells and the synthesis of the globin chains of hemoglobin in those
cells (3,5). The result is erythroid hyperplasia (2).
Despite the stimulatory effect of thyroid hormone on erythropoiesis, most patients with
thyrotoxicosis have normal hemoglobin concentrations and hematocrit values (1,2,6,7). This
may be explained in part by an increase in plasma volume, which is a frequent finding, as well
as shortened red blood cell survival (2,5). Red cell morphology is usually normal, but the cells
tend to be slightly smaller than normal (7). Some patients seem to have ineffective
erythropoiesis, based on increased numbers of sideroblasts and increased amounts of
hemosiderin in their marrow (8). However, other patients have low marrow iron stores (2).
Serum iron concentrations are usually normal, those of transferrin tend to be low, and those of
ferritin high (9).
Pernicious anemia occurs in 1% to 3% of patients with thyrotoxicosis, and 15% to 20% have
high serum concentrations of parietal cell antibodies (6,10). These abnormalities are linked
with Graves' thyrotoxicosis, not other types of thyrotoxicosis, and probably reflect the
patients' vulnerability to autoimmune disorders rather than some interaction between thyroid
hormone and vitamin B12 metabolism. In fact, patients with both type 1 diabetes mellitus and
Graves' disease may be at even higher risk for the development of pernicious anemia (11). In
addition to immunologic mechanisms, patients with thyrotoxicosis may have increased
requirements for vitamin B12 and folate (3,10). Serum vitamin B12 concentrations in patients
with thyrotoxicosis who do not have pernicious anemia are lower than in normal subjects and
increase after successful antithyroid therapy (12). Serum folate concentrations are high or
normal in patients with thyrotoxicosis (2,3,12).
Thyroid hormone also exerts effects within erythrocytes. Thyrotoxic patients have high red
blood cell 2,3-diphosphoglycerate concentrations, which shifts the oxyhemoglobin curve to
the right (1,3,5). This change, like the stimulation of erythropoiesis, augments oxygen
delivery to peripheral tissues. Red cell Na+,K+-ATPase activity is low in thyrotoxicosis, due to
a decrease in the number of pump units per cell; therefore, the red cell sodium concentration
is increased. In contrast, Na+,K+-ATPase activity is increased in most other tissues, including
leukocytes, and indeed the increase is thought to contribute importantly to the increases in
oxygen consumption and substrate utilization that are characteristic of thyrotoxicosis (see
Chapter 38).
Red blood cell zinc concentrations are low in patients with thyrotoxicosis, as are the red cell
concentrations of the zinc-containing enzyme carbonic anhydrase (13). In a study of patients
with thyrotoxicosis before and during treatment, red cell zinc concentration and serum
thyroxine (T4) and triiodothyronine (T3) concentrations were inversely correlated, but during
treatment red cell zinc concentrations increased more slowly than serum T4 and T3
concentrations decreased, suggesting that red cell zinc concentrations reflect mean serum T4
and T3 concentrations over time, and therefore that measurements of red cell zinc could serve
as a marker of time-integrated serum T4 and T3 concentrations (13).
In summary, erythropoiesis is increased in patients with thyrotoxicosis, largely to meet the
need to increase oxygen delivery to peripheral tissues. Nevertheless, 10% to 25% of patients
have anemia, which may be normocytic, microcytic, or macrocytic, but it is rarely severe
(1,3,5,6,7). Among patients who are anemic, the causes include ineffective erythropoiesis,
iron deficiency, vitamin B12 deficiency, and folate deficiency; among these causes only
ineffective erythropoiesis is likely to be a direct effect of thyrotoxicosis.
Leukocytes
Most patients with thyrotoxicosis have normal leukocyte counts, normal or slightly low
granulocyte counts, and
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normal or slightly increased lymphocyte counts (7,14,15,16,17,18). Furthermore, a few


thyrotoxic patients have lymphoid enlargement and splenomegaly, and rare patients have
thymic enlargement; these changes seem to occur mostly in patients with Graves'
thyrotoxicosis, implying they are in some way related to immune activation rather than to
thyrotoxicosis. No consistent abnormalities in the proportions of circulating B and T
lymphocytes have been found in patients with Graves' thyrotoxicosis (19), but lymphocyte
function may be abnormal, in that the cytotoxic activity of natural killer cells is lower in these
patients than in normal subjects or patients with toxic nodular goiter (15).
Most patients with thyrotoxicosis caused by Graves' disease have normal granulocyte counts,
but some have granulocytopenia (5,14,17). The cause is unknown. In a study of 17 patients
with Graves' thyrotoxicosis, 8 had reduced bone marrow reserves of granulocytes, although
only 1 had granulocytopenia (16). Although antineutrophil antibodies may be detected in up
to 50% of patients with Graves' thyrotoxicosis, the contribution of the antibodies to the
observed granulocytopenia is unclear (20). In a study of 63 patients with thyrotoxicosis, 17
(27%) had a granulocyte count less than 2,000/mm3, 36 (57%) had a count of 2,000 to
4,000/mm3 (2 to 4Ă—109/L), and 10 (16%) had a count of greater than 4,000/mm3 (4Ă—
109/L) (16); the patients' mean granulocyte count was 3,100/mm3 (3.1Ă—109/L), as compared
with 3,600/mm3 (3.6Ă—109/ L) in normal subjects (17). In the patients the granulocyte counts
were correlated positively with serum concentrations of granulocyte colony-stimulating factor
(G-CSF), which were on average slightly higher than in normal subjects, but not with their
serum free T4 concentrations. In patients with granulocyte counts of less than 2,000/mm3 (2Ă
—109/L), the counts tended to increase after initiation of methimazole therapy. The three
patients whose granulocyte counts declined transiently during methimazole therapy (none had
agranulocytosis) had no change in serum G-CSF concentrations.
In another study of 37 patients treated with carbimazole in doses of 25 or 100 mg/day,
granulocyte counts increased during the first 2 weeks of therapy in the former group and
decreased in the latter group; however, there were no differences between the groups
subsequently (18). Thus, the granulocyte count can increase during antithyroid drug
treatment, even in patients with granulocytopenia (see Chapter 45).
HEMOSTASIS
Platelets
An occasional patient with thyrotoxicosis, nearly always caused by Graves' disease, has
clinically important thrombocytopenia [platelet count < 100,000/mm3 (100Ă—109/L)], and
many [42% in one study (21)] have platelet counts of less than 150,000/mm3 (150Ă—109/L)
(22). Only rare patients, however, have clinical manifestations of thrombocytopenia or other
disturbances in coagulation.
The thrombocytopenia has several causes (23). First, some patients with Graves'
thyrotoxicosis have antiplatelet antibodies; they thus can be said to have autoimmune
thrombocytopenia purpura (24). Its incidence may be increased in patients with Graves'
disease (25), and it may precede the onset of thyrotoxicosis (26). In a study of 25 patients
with Graves' thyrotoxicosis, 11 (44%) had high serum levels of platelet-bound
immunoglobulin G (IgG) (24). Among the 11 patients, most had easy bruising or bleeding,
and 3 had thrombocytopenia. Because of this association between autoimmune
thrombocytopenia and Graves' disease, screening for hyperthyroidism should be considered in
patients with unexplained thrombocytopenia (27). Another possible explanation for
thrombocytopenia in patients with Graves' thyrotoxicosis is binding of thyrotropin (TSH)
receptor–stimulating or other thyroid antibodies to truncated actin-binding protein on
platelets, which links both the glycoprotein and the high-affinity Fc receptor for
immunoglobulin G on the platelet membrane to the cytoskeleton of platelets, providing a
mechanism whereby the antibodies could bind to platelets and accelerate their destruction
(23).
Other factors that may contribute to thrombocytopenia in these patients are the thyrotoxicosis
itself, which may increase the phagocytic activity of the reticuloendothelial system, including
the spleen, and splenomegaly. Either would accelerate the clearance of platelets, whether
sensitized or not (21,22,28).
All these effects are to some extent counterbalanced by increased production of platelets. The
number of megakaryocytes in the bone marrow may be increased (29). The number of
reticulated (young) platelets in the circulation is increased. These platelets are larger than
more mature ones, and thus mean platelet volume is increased (28,30).
Platelet counts usually increase, platelet size decreases, and the amount of platelet-associated
immunoglobulin G (IgG) decreases during antithyroid therapy (22,31). Patients with severe
thrombocytopenia have been given concomitant glucocorticoid therapy (26), as would be
done for thrombocytopenia alone. Antithyroid drugs may have immunosuppressive as well as
antithyroid actions (see Chapter 45), which may reduce the production of IgG capable of
binding to platelets.
Thyrotoxicosis may also alter platelet function; platelet aggregation in response to adenosine
diphosphate (ADP), collagen, and ristocetin is decreased (32,33). These changes in platelet
function may be due to inhibition of myosin light chain kinase, an enzyme that stimulates
platelet contractile proteins (34). These abnormalities also improve during antithyroid therapy
(32,33).
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Clotting Factors and Warfarin Therapy


In thyrotoxicosis, the rate of clearance of most if not all coagulation factors is increased (35).
However, the plasma concentrations of most of these factors are normal, except for small
decreases in factor II concentrations and increases in factor VIII concentrations (36,37,38).
Some thyrotoxic patients have shortened partial thromboplastin times, perhaps resulting from
the increase in plasma factor VIII concentrations (36,38). Factor VIII deficiency due to an
acquired circulating antibody that inhibited factor VIII coagulant activity was reported in two
patients with Graves' thyrotoxicosis who presented with spontaneous bleeding (39,40). Serum
concentrations of thrombomodulin, an endothelial surface glycoprotein that serves as a
thrombin receptor, are high in patients with thyrotoxicosis (41).
The sensitivity of thyrotoxic patients to the anticoagulant effects of warfarin is increased. In
one study in which thyrotoxic patients were given a single dose of warfarin, the decrease in
both factors II and VII was greater and the increase in prothrombin time was greater before
than after antithyroid treatment, but the responses of factors IX and X were similar (36). The
explanation for the increased effect of warfarin in thyrotoxicosis is multifactorial, probably
involving both more rapid clearance of clotting factors and reduced plasma protein binding of
the drug. However, the results of pharmacokinetic studies of warfarin in thyrotoxic patients
have been conflicting. In one study, the single-dose warfarin plasma half-life, plasma
clearance, and volume of distribution were similar in patients studied when they were
thyrotoxic and again when they were euthyroid (36); on the other hand, in a thyrotoxic patient
receiving chronic warfarin therapy (5 mg/day), the plasma free warfarin concentration was
high (37), consistent with decreased plasma protein binding of the drug (42). In addition,
patients with thyrotoxicosis may be relatively resistant to reversal of warfarin-induced
hypoprothrombinemia by vitamin K. Therefore, patients with thyrotoxicosis treated with
warfarin may require lower doses.
Anticardiolipin Antibodies
Anticardiolipin antibodies have been found in the serum of patients with Graves'
thyrotoxicosis, especially those with coexisting ophthalmopathy (43,44). These antibodies,
especially those belonging to the immunoglobulin G isotype, may be associated with
hypercoagulable states. With antithyroid therapy, the antibody concentrations decreased (44).
Fortunately, thromboembolic events, the primary antiphospholipid syndrome, and recurrent
abortions are rare occurrences in patients with Graves' thyrotoxicosis, and the presence of
these antibodies may be a nonspecific marker of immune system activation (45).

Thyrotoxic Storm
Leonard Wartofsky
Thyrotoxic storm or crisis is a rare, life-threatening syndrome characterized by exaggerated
clinical manifestations of thyrotoxicosis. Its incidence is not precisely known because there
are no widely accepted criteria for its diagnosis. However, a scoring system to indicate the
diagnosis has been proposed (1) based on signs and symptoms and is proving useful (Table
43.1). It appears that the syndrome is much less common today than in the past, due to earlier
diagnosis and treatment of thyrotoxicosis, and storm may account for no more than 1% to 2%
of hospital admissions for thyrotoxicosis. On the basis of routine thyroid function tests, most
patients with thyrotoxic storm are indistinguishable from those with uncomplicated
thyrotoxicosis. Therefore, the diagnosis typically is a clinical one, based on the severity of the
symptoms and signs of thyrotoxicosis and presence of functional decompensation of one or
more organ systems in a thyrotoxic patient. Because of the potential high mortality, it is often
necessary to begin treatment without waiting for biochemical confirmation of the diagnosis of
thyrotoxicosis.
TABLE 43.1. DIAGNOSTIC CRITERIA FOR THYROTOXIC CRISIS
Points
Thermoregulatory dysfunction
Temperature (°F): 99–99.9 5
100–100.9 10
101–101.9 15
102–102.9 20
103–103.9 25
≥104 30
Central nervous system effects
Absent 0
Mild agitation 10
Delirium, psychosis, lethargy 20
Seizure or coma 30
Gastrointestinal dysfunction
Absent 0
Diarrhea, nausea, vomiting, or abdominal pain 10
Unexplained jaundice 20
Cardiovascular dysfunction
Tachycardia (beats/min): 90–109 5
110–119 10
120–129 15
130–139 20
≥140 25
Congestive heart failure: Absent 0
Mild (edema) 5
Moderate (bibasilar rales) 10
Severe (pulmonary edema) 15
Atrial fibrillation: Absent 0
Present 10
History of precipitating event (surgery, infection, etc.)
Absent 0
Present 10
Points are assigned as applicable and the score totaled. When it is not possible to distinguish a
finding due to an intercurrent illness from that of thyrotoxicosis, the higher point score is
given so as to favor empiric therapy. Interpretation: Based on the total score, the likelihood of
the diagnosis of thyrotoxic storm is: unlikely, < 25; impending, 25–44; likely, 45–60;
highly likely, >60.
Adapted from Burch HB, Wartofsky L. Life-threatening thyrotoxicosis: thyroid storm.
Endocrinol Metab Clin North Am 1993;22:263, with permission
The cardinal manifestations of thyrotoxic storm may not all be present or may be present in
variable degree, and can include fever (temperature usually >102°F), tachycardia (out of
proportion to the fever), gastrointestinal dysfunction (including nausea, vomiting, diarrhea,
and, in severe cases, jaundice), and central nervous system (CNS) dysfunction, varying from
marked hyperirritability and anxiety to confusion to apathy and even coma. Prompt diagnosis
and vigorous therapy are required to avoid a fatal outcome; the mortality rates of hospitalized
patients have ranged from 10% to 75% (1,2,3,4).
CLINICAL FEATURES
Most patients with thyrotoxic storm have rather obvious symptoms and signs of
thyrotoxicosis, including goiter and, in the presence of Graves' disease, ophthalmopathy,
although it can occur in patients with masked or apathetic thyrotoxicosis (5). There is usually
a several-month history of untreated or partially treated thyrotoxicosis, but in an occasional
patient the onset of thyrotoxicosis seems to be recent. Typically, those cases of more recent
onset will be more rapidly progressive in severity of manifestations.
Two types of events have been associated with the precipitation of thyrotoxic crisis (Table
43.2). One is an intercurrent illness or injury that exacerbates the effects of thyrotoxicosis
either systemically or on one or more particular organ systems. The other, now rare, is an
acute event that suddenly increases thyroid secretion. This latter situation is best exemplified
by the occurrence of thyrotoxic storm soon after thyroidectomy, which was relatively
common before the need for preoperative antithyroid therapy was recognized. The presumed
explanation was increased thyroxine (T4) and triiodothyronine (T3) release caused by
manipulation of the thyroid gland, compounded by the systemic effects of surgical stress. The
rare occurrence of thyrotoxic storm after radioiodine therapy for thyrotoxicosis is the modern
counterpart of this phenomenon.
TABLE 43.2. EVENTS ASSOCIATED WITH THE ONSET OF THYROTOXIC
STORM
Infection
Other acute medical illness
Acute emotional stress
Acute psychosis
Nonthyroid surgery
Parturition
Trauma
Thyrotoxicosis factitia
After radioiodine therapy
Postthyroidectomy
After high-dose iodine administration
Iodinated radiographic contrast agent administration
Discontinuation of antithyroid drug therapy
Vigorous palpation of thyroid gland
Many illnesses and trauma, including the trauma of surgery, can precipitate thyrotoxic storm
in patients with previously undiagnosed or poorly treated thyrotoxicosis, and storm has been
seen following the trauma of an automobile accident (6). The most common precipitating
event now is probably an infection, and in a patient with thyrotoxicosis and infection it is
difficult if not impossible to determine whether fever and tachycardia herald impending crisis
or merely reflect the infection. Excessive diaphoresis with high fever out of proportion to the
infection may be a clue to the presence of thyrotoxic storm. Indeed, when it is not recognized
and treated, the fever may reach an extremely high and life-threatening level. An exception to
this may be the elderly “apathetic” patient or those with concomitant pituitary or adrenal
insufficiency (7). Symptoms of CNS dysfunction indicative of a metabolic encephalopathy,
with anxiety, emotional lability, restlessness, agitation, confusion, psychosis, and coma
(5,8,9,10), are common, and are important further clues to the diagnosis. In one case,
thyrotoxic storm was associated with status epilepticus and stroke (11), and in another with
bilateral basal ganglia infarction (12). Storm due to excessive ingestion of thyroid hormone
(thyrotoxicosis factitia) has been reported (13) but must be extremely rare.
In addition to marked sinus tachycardia, other atrial tachyarrhythmias may be present, as may
symptoms and signs of congestive heart failure. Although the latter is
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more likely to occur in elderly patients with underlying heart disease, it can occur in relatively
young or middle-aged patients with no known antecedent (or subsequently demonstrable)
heart disease. Systolic hypertension with widened pulse pressure is likely to be noted in most
patients, at least initially, although some patients have postural hypotension, particularly those
with volume depletion due to vomiting or diarrhea, and vascular collapse may supervene.
Other gastrointestinal manifestations include presentation as an acute abdomen (14) or
intestinal obstruction (15), or with diffuse abdominal pain, hepatomegaly, splenomegaly, and
various abnormalities in liver function. The liver may be tender, as a result of either
congestion or hepatic necrosis. The presence of jaundice is a poor prognostic sign.
LABORATORY FINDINGS
Serum total T4 and T3 concentrations and thyroid radioiodine uptake values are high in
patients with thyrotoxic storm, but not necessarily more so than in patients with
uncomplicated thyrotoxicosis (16). Serum free T4 and T3 concentrations are also high, and
may be on average slightly higher than in patients with uncomplicated thyrotoxicosis (17). On
the other hand, serum T3 concentrations may be normal in patients who have been sick for
more than a few days, due to the decrease in extrathyroidal conversion of T4 to T3 that occurs
in many nonthyroidal illnesses (18,19,20,21,22) (see section on nonthyroidal illness in
Chapter 11).
In a patient with previously undiagnosed thyrotoxicosis, the most rapid confirmation of the
diagnosis may be obtained by measuring thyroid radioiodine uptake 2 hours after
administration of the radioiodine or thyroid pertechnetate uptake 20 or 30 minutes after
administration of pertechnetate (see Chapter 12). It should be possible to obtain the results of
serum T4 and thyrotropin (TSH) determinations in a few hours on an emergency basis in
many hospitals.
In any event, given the high mortality of untreated thyrotoxic storm, the presence of severe
clinical thyrotoxicosis with high fever and marked tachycardia and some other illness in a
patient with a goiter, with or without ophthalmopathy, should be considered as sufficient
support for the diagnosis of thyrotoxic crisis to warrant immediate initiation of therapy. In
most patients the cause of the thyrotoxicosis is Graves' disease, but thyrotoxic storm has been
reported in patients with other causes of thyrotoxicosis (23,24).
Patients with thyrotoxic storm may have mild to moderate hyperglycemia, probably caused by
increased glycogenolysis and catecholamine-mediated inhibition of insulin release. A
leukocytosis with a mild shift to the left is common,
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even in the absence of infection, whereas other hematologic values tend to be normal. Serum
electrolyte concentrations usually are normal, but mild hypercalcemia is common, as a result
of both hemoconcentration and thyroid hormone–stimulated bone resorption. Serum lactate
dehydrogenase, aspartate and alanine aminotransferase, and bilirubin concentrations may be
high as a result of hepatic dysfunction, and serum alkaline phosphatase concentrations may be
high as a result of both increased osteoblastic activity and hepatic dysfunction. Serum cortisol
concentrations should be high, and as in any other acute illness, a normal value should be
interpreted as being inappropriately low. Even in the absence of adrenal insufficiency, adrenal
reserve may be reduced in patients with thyrotoxic storm because of the inability of the
adrenal gland to increase cortisol secretion sufficiently to meet the need for more cortisol in
the presence of the increase in cortisol clearance caused by thyrotoxicosis (see Chapter 37).
PATHOGENESIS
The mechanism by which acute illness or injury precipitates thyrotoxic storm is poorly
understood, and it is likely that several factors are important. The magnitude of the increase in
thyroid secretion alone does not appear to be critical; many less ill thyrotoxic patients have
equally high serum T4 and T3 concentrations, and children who accidentally ingest large doses
of T4 and have very high serum T4 and T3 concentrations do not have thyrotoxic storm (25).
Therefore, an acute increase in release of T4 or T3 from the thyroid is not thought to be
important in the pathogenesis of most cases of thyrotoxic storm, but this mechanism probably
does play a role in those cases that have been reported after radioiodine therapy (2),
thyroidectomy, discontinuation of an antithyroid drug or lithium (26,27), or administration of
iodine or iodinated radiographic contrast agents (18). Whether it is the discontinuation of
antithyroid drugs prior to radioiodine therapy or the radioiodine itself that may be the
precipitant of thyroid storm remains somewhat controversial (28,29). Furthermore, there may
be rapid improvement after abrupt reductions in serum T4 and T3 concentrations, such as may
be achieved with peritoneal dialysis or plasmapheresis (30,31,32,33). Therefore, although
serum total T4 and T3 concentrations may not be dramatically higher in patients with
thyrotoxic storm than those in otherwise uncomplicated thyrotoxicosis, the concentrations in
the former patients could have increased acutely before the onset of the storm (34).
Furthermore, many acute illnesses cause a decrease in protein binding of T4 and T3 in serum,
due to decreases in binding protein production (particularly transthyretin) or inhibitors of T4
and T3 binding to protein (35), resulting in a relative increase in the percentage and absolute
serum concentrations of free T4 and T3. Transient increases in serum free T4 and T3
concentrations have been reported in patients with thyrotoxic storm (17,36).
Many of the symptoms and signs of severe thyrotoxicosis mimic those of catecholamine
excess (37,38) (see Chapter 38), suggesting a role for sympathetic nervous system activation
in thyrotoxic storm. Although serum catecholamine concentrations and urinary catecholamine
excretion are normal, arguing against the concept of increased sympathetic activity per se,
there is little doubt that in patients with thyrotoxic storm, dramatic clinical improvement
follows the administration of drugs that either deplete tissue catecholamines, such as reserpine
(39), or block β-adrenergic receptors, such as propranolol. Indeed, treatment with propranolol
or other β-adrenergic antagonist drugs may be responsible for the improvement in survival in
recent years, notwithstanding a report that customarily used doses of propranolol may not
prevent the occurrence of thyrotoxic storm (40).
Another phenomenon postulated to play a role in the pathogenesis of thyrotoxic storm is
augmentation of peripheral cellular responses to thyroid hormone, which may be especially
relevant to those patients with hypoxemia, ketoacidosis, lactic acidosis, or infection. In them,
partial uncoupling of the process of oxidative phosphorylation leading to generation of
adenosine triphosphate could result in excess substrate utilization, oxygen consumption, and
thermogenesis, and therefore hyperthermia. The excess heat is partially dissipated by
increased sweating and cutaneous vasodilatation, which are common in severe thyrotoxicosis.
TREATMENT
There are four components of treatment for patients with thyrotoxic storm (Table 43.3), their
relative importance varying among different patients (1). First, an antithyroid drug must be
given to decrease thyroidal production and secretion of T4 and T3. Second, systemic
disturbances such as fever and hypovolemia must be ameliorated by appropriate treatment.
Third, the tissue effects of the high serum T4 and T3 concentrations should be ameliorated by
administration of a β-adrenergic antagonist drug. Fourth, any underlying precipitating illness
or injury must be treated appropriately.
TABLE 43.3. TREATMENT OF THYROTOXIC STORM
Reduction of thyroid hormone production and secretion
Inhibition of T4 and T3 synthesis
Propylthiouracil, methimazole
Inhibition of T4 and T3 secretion
Inorganic iodide (potassium iodide, Lugol's solution)
Radiographic contrast agents (sodium ipodate, iopanoic acid)
Lithium carbonate
Thyroidectomy
Therapy directed against systemic disturbances
Treatment of fever
Acetaminophen
External cooling
Correction of volume depletion and poor nutrition
Intravenous fluid and electrolyes
Glucose (calories)
Vitamins
Supportive therapy
Oxygen
Vasopressor drugs
Treatment for congestive heart failure (diuretics, digoxin)
Amelioration of the peripheral actions of thyroid hormone
Inhibition of extrathyroidal conversion of T4 to T3
Propylthiouracil
Radiographic contrast agents (sodium ipodate, iopanoic acid)
Glucocorticoids
Propranolol or other β-adrenergic antagonist drugs
Removal of T4 and T3 from serum
Cholestyramine, plasmapheresis, hemodialysis, hemoperfusion
Treatment of any precipitating or underlying illness
T3, triiodothronine; T4, thyroxine.
All patients with thyrotoxic storm should be treated in an intensive care unit because of the
need for close monitoring of temperature, cardiac function and fluid and electrolyte balance.
Serious consideration should be given to insertion of a Swan-Ganz catheter to monitor central
hemodynamics in patients with prominent cardiovascular problems.
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Therapy to Reduce Thyroid Hormone Synthesis and Secretion


A thionamide antithyroid drug, either propylthiouracil (PTU) or methimazole (MMI), is given
to block T4 and T3 synthesis (see Chapter 45). No parenteral preparations of these drugs are
available; therefore, they must be given by mouth or by nasogastric tube. Rectal
administration also has been used successfully in a few patients (41,42,43,44). It is customary
to give high doses of the drug, for example, 200 to 250 mg PTU every 4 hours or 20 mg MMI
every 4 hours. PTU is favored because it not only inhibits T4 and T3 synthesis, but also
inhibits extrathyroidal conversion of T4 to T3, thereby reducing serum T3 concentrations and
perhaps also the clinical manifestations of thyrotoxicosis more rapidly than MMI.
These drugs do not inhibit release of already synthesized T4 and T3 from the thyroid, but that
can be accomplished by administration of inorganic iodide (45) (see Chapter 45). It may be
given either orally as Lugol's solution or as a saturated solution of potassium iodide (eight
drops every 6 hours). These doses provide several hundred milligrams of iodide daily, much
more than is needed for effective inhibition of thyroglobulin proteolysis and T4 and T3 release.
Potassium iodide for intravenous administration is no longer available, although it probably
could be prepared quickly in a hospital pharmacy.
The antithyroid drug should be given about an hour before the iodide is given, because a
sudden influx of iodide into the thyroid can increase T4 and T3 synthesis and therefore
increase the stores of the two hormones, thereby prolonging the period of thyrotoxicosis.
When iodide is administered in conjunction with a high dose of an antithyroid drug, serum T4
and T3 concentrations decrease substantially within a few days and approach the normal range
in 5 to 7 days (45).
Another approach is to administer a lipid-soluble radiographic contrast agent such as sodium
ipodate and iopanoic acid instead of iodide. These agents, which must be given orally, contain
organically bound iodine. The iodide released by deiodination of the agent inhibits T4 and T3
release, and the agents themselves inhibit the extrathyroidal conversion of T4 to T3 and
perhaps also binding of T3 to its nuclear receptors (see section on effects of drugs and other
substances on thyroid hormone synthesis and metabolism in Chapter 11). Administration of
one of these agents can lead to rapid clinical and biochemical improvement (46). These agents
may also be useful in the therapy of massive acute thyroid hormone poisoning secondary to
ingestion of T4, especially in children, due to the peripheral inhibition of the conversion of T4
to T3. A loading dose of 2 g is usually given, followed by 1 g daily. These agents are no
longer available in the U.S.
In patients who may be allergic to iodine, lithium carbonate may be used as an alternative
drug to inhibit T4 and T3 synthesis (47,48). Lithium also may be given as an alternative drug
in thyrotoxic patients known to have had serious toxic reactions (e.g., hepatitis or
agranulocytosis) to PTU or MMI; however, a history of minor allergic reactions to either PTU
or MMI, such as rash, should not interdict their use in a critically ill patient with thyrotoxic
storm. Lithium should be administered initially in a dose of 300 mg every 6 hours, with
subsequent adjustment of dosage as necessary to maintain serum lithium concentrations at
about 1 mEq/L. Finally, thyroidectomy may be done on an emergent basis (49,50).
Therapy Directed Against Systemic Disturbances
Fever should be promptly treated with an antipyretic drug, preferably acetaminophen rather
than salicylate. The latter competitively inhibits T4 and T3 binding to serum proteins and
therefore increases serum free T4 and T3 concentrations, which might theoretically temporarily
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worsen the thyrotoxicosis. External cooling with alcohol sponging, ice packs, or a
hypothermia blanket also may be used.
Fluid losses caused by fever and diaphoresis, as well as by vomiting or diarrhea, when
present, should be replaced, primarily with isotonic saline containing 5% or 10% glucose and
supplemental vitamins, to avoid vascular collapse and provide nutritional support. Care must
be taken to avoid overreplacement in older patients with cardiac disease. Hypotension
refractory to fluid resuscitation has been reported (51). In such patients, vasopressor drug
therapy may be indicated. Hypercalcemia, if present, usually can be reversed by volume
repletion.
Congestive heart failure should be treated by administration of furosemide or
hydrochlorothiazide and digoxin, especially in patients with atrial fibrillation. Somewhat
higher than usual doses of digoxin may be needed because its clearance is accelerated in
patients with thyrotoxicosis (see Chapter 31). In patients with marked tachycardia and
congestive heart failure, slowing of the rate with propranolol or a related drug often alleviates
the heart failure, notwithstanding the negative inotropic effects of these drugs (see Chapter
31).
High doses of a glucocorticoid have long been given on empirical grounds because of the
postulated risk of relative adrenal insufficiency, as discussed above. High doses also inhibit
extrathyroidal conversion of T4 to T3, and in patients with Graves' thyrotoxicosis they also
directly inhibit thyroid secretion, although these two actions are probably not important in
patients receiving aggressive antithyroid therapy as described above. Hydrocortisone is often
given in an initial dose of 200 or 300 mg, followed by 100 mg every 8 hours for several days,
after which the dose should be tapered quickly, but equivalent doses of dexamethasone or
methylprednisolone can be given instead. In one case, thyrotoxic storm returned when
glucocorticoid therapy was discontinued after initial clinical improvement (52).
Therapy Directed Against the Peripheral Actions of Thyroid Hormone
Many of the peripheral manifestations of thyrotoxic storm can be ameliorated rapidly by
administration of propranolol or another β-adrenergic antagonist drug. The use of these drugs
evolved from the earlier demonstration that drugs such as reserpine and guanethidine could
blunt the apparently increased sympathetic activity in patients with thyrotoxicosis (29,53,54).
Propranolol is the drug most commonly given today, at least in the United States. High doses
are usually given to patients with thyrotoxic storm, for example, 60 to 80 mg orally every 6
hours (55,56), to achieve rapid adrenergic blockade and because drug clearance is increased in
patients with severe thyrotoxicosis.
Propranolol also may be given intravenously. By that route, the initial dose should be 0.5 to 1
mg given over 10 minutes while the patient's cardiac rhythm is continuously monitored.
Subsequently, 1 to 3 mg may be given intravenously over 10 to 15 minutes every several
hours, until propranolol given orally at the start of treatment takes effect or oral therapy can
be initiated (57). The primary role of propranolol is to attenuate the effects of catecholamines,
but it is also a weak inhibitor of extrathyroidal conversion of T4 to T3. However, this
inhibition occurs over about a week, and clearly does not account for the beneficial effects of
propranolol in patients with thyrotoxic storm.
The most dramatic effects of β-adrenergic blockade are on the cardiovascular system.
Effective doses of either orally or intravenously administered propranolol result in rapid
reduction in heart rate and an increase in cardiac output, if the latter was low because of the
rapid rate (58). Patients who previously seemed refractory to digoxin and diuretic therapy
may respond rapidly after initiation of propranolol therapy. If there is an underlying
cardiomyopathy, however, propranolol may have the adverse effect of reducing sympathetic
drive to the myocardium, and would need to be given cautiously in such patients.
Other beneficial effects of propranolol in thyrotoxic storm include improvement in agitation,
psychotic behavior, tremor, diarrhea, fever, and diaphoresis. In some patients, there may be
relative risks or contraindications to propranolol therapy, for example, in patients being
treated for diabetes mellitus, in whom it may mask some of the symptoms of hypoglycemia,
or in patients with asthma, in whom it may exacerbate bronchospasm. Untoward bradycardia
caused by propranolol may be reversed by administration of atropine, and isoproterenol
should be given to counteract bronchospasm or failing left ventricular function. In patients at
risk for adverse effects of propranolol, a more cardioselective β-adrenergic antagonist drug
may be given. A very short-acting β-adrenergic antagonist, esmolol, can be given
intravenously instead of propranolol. The initial dose is 0.25 to 0.5 mg/kg given in 5 to 10
minutes, followed by a continuous infusion of 0.05 to 0.1 mg/kg/min (59,60).
Reserpine and guanethidine, which were the first sympatholytic drugs used for treatment of
patients with thyrotoxic storm, are no longer used. As compared with propranolol and other
β-adrenergic antagonist drugs, they are both less effective and more likely to have adverse
effects, particularly hypotension and CNS depression.
Several methods to remove T4 and T3 from the serum have been devised. Among them the
simplest is to administer cholestyramine orally, to interrupt the enterohepatic circulation of T4
and T3 by binding the hormones in the gastrointestinal tract (61). Serum T4 and T3
concentrations also can be reduced by either peritoneal dialysis or plasmapheresis (31,32,33).
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Hemoperfusion through a bed of resin or charcoal, to which T4 and T3 will bind, also has been
demonstrated to be effective experimentally (62,63). These are cumbersome procedures and
should be considered only in exceptional cases.
L-carnitine is a quaternary amine that acts to inhibit thyroid hormone action by reducing
nuclear binding of T3 and has been proposed as a therapy for both thyrotoxicosis and thyroid
storm. Carnitine along with low-dose methimazole was effective in one patient who survived
three sequential episodes of thyroid storm (64).
Therapy Directed Against a Precipitating Illness
All patients with thyrotoxic storm should be evaluated carefully for the presence of another
illness that may have precipitated or at least exacerbated the patient's thyrotoxicosis, and
appropriate treatment initiated. In some patients, for example those with an infection or
trauma, the problem is obvious, but in others it is less so and can be uncovered only by
thorough evaluation. This is especially important in patients who are obtunded or psychotic,
and therefore may not be able to provide relevant historical information.
Most patients treated as described above improve considerably within 12 or 24 hours. The
pulse rate slows, fever subsides, and mental status improves. With continued improvement,
antipyretic and glucocorticoid therapy can be reduced and discontinued, and oral hydration
and nutrition can be initiated. Subsequently, attention should be turned to further treatment of
thyrotoxicosis. If the patient has Graves' thyrotoxicosis, as is usually the case, the antithyroid
drug therapy can be continued in the hope that a remission of Graves' disease will occur, but
in general radioiodine therapy or thyroidectomy is preferred for patients who have had
thyrotoxic storm. Because virtually all patients are treated with inorganic iodide, an iodine-
containing radiographic contrast agent, or both, radioiodine therapy cannot be given for
several weeks or months. Given that radioiodine therapy must be delayed, thyroidectomy may
be more expedient, but it should not be undertaken until the patient has been euthyroid for
several weeks (see Chapter 45).
There has been a revival of interest in surgical approaches to thyroid storm, as noted above
(49,50) although thyroidectomy in a severely thyrotoxic patient has been considered risky
until the thyrotoxicosis was brought under control. Proponents of thyroidectomy point to the
relatively long latent period before improvement and the potential high mortality with medical
therapy. Scholz et al. (50), after reviewing their experience with 10 patients and others treated
by thyroidectomy in the literature, noted a mortality of only 10%. They concluded that
thyroidectomy should be considered for storm, particularly if the usual therapies outlined
above do not lead to significant improvement within 12 to 24 hours.