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Thyroid Disorders: Hyperthyroidism and Thyroid Storm
Introduction
Thyroid hormone affects all organ systems, and is responsible for increasing
metabolic rate, heart rate, ventricle contractility, as well as muscle and central
nervous system excitability. Two major types of thyroid hormones are thyroxine (T4 )
and triiodothyronine (T3). T4 is the major form of thyroid hormone. The ratio of T 4 to
T3 released in the blood is 20:1. Peripherally, T4 is converted to the active T3, which is
three to four times more potent than T4 .
Hyperthyroidism refers to excess circulating hormone resulting only from thyroid
gland hyperfunction whereas thyrotoxicosis refers to excess circulating thyroidhormone originating from any cause (including thyroid hormone overdose).
Thyroid storm is the extreme manifestation of thyrotoxicosis. This is an acute,
severe, life-threatening state of thyrotoxicosis caused either by adrenergic
hyperactivity or altered peripheral response to thyroid hormone following the
presence of one or more precipitants.
Epidemiology
In the U.S., the overall incidence of hyperthyroidism is estimated to be between
0.05% to 1.3%, with the majority being subclinical in terms of presentation.1
Among
hospitalized thyrotoxicosis patients, the incidence of thyroid storm has been noted
to be
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Causes of Hyperthyroidism or Thyrotoxicosis
Table 224-1 Causes of Hyperthyroidism: Primary and Secondary Hyperthyroidism
Primary Hyperthyroidism
Graves disease (toxic diffuse
goiter) (Figure 224-0.1)
Most common of all hyperthyroidism (85% of all cases)
Associated with diffuse goiter, ophthalmopathy, and local
dermopathy
Toxic multinodular goiter Second most common cause of hyperthyroidism
Toxic nodular (adenoma)
goiter (Figure 224-0.2)
An enlarged thyroid gland that contains a small rounded mass or
masses called nodules with overproduction of thyroid hormone
Secondary Hyperthyroidism
Thyrotropin-secreting pituitary
adenoma
Thyroid gland stimulated to produce hormones
Thyroiditis Inflammation of the thyroid gland.
Hashimoto thyroiditis Initially gland is overactive (hyperthyroidism state) but this is
usually followed by a state of hypothyroidism
Subacute painful thyroiditis
(de Quervain thyroiditis)
Subacute painless thyroiditis
Radiation thyroiditis
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Table 224-2 Other Causes of Hyperthyroidism
Nonthyroidal Disease
Ectopic thyroid tissue
(struma ovarii)/teratoma
A rare form of mature teratoma that contains mostly thyroid
tissue.Metastatic thyroid cancer Stimulates production of thyroid hormones.
Human chorionic
gonadotropin
Secreting hydatidiform mole.
Drug-Induced
Iodine Iodine-induced thyrotoxicosis (calledJod-Basedow disease).
After treatment of endemic goiter patients with iodine or
stimulation of thyroid hormones from use of iodine-
containing agents like radiographic contrast agents.
Amiodarone Contains iodine. May cause either thyrotoxicosis or
hypothyroidism.
-Interferon
During treatment for other diseases, such as viral hepatitis
and human immunodeficiency virus infection.
Interleukin-2
Excessive thyroid
hormone ingestion
Thyrotoxicosis factitia Munchausen-like; thyroid hormone is taken by patient to fake
illness.
Ingestion of meat
containing beef thyroid
tissue
Cow thyroid tissue contains thyroid hormones.
Other causes may include nonthyroidal diseases caused by production of thyroid
hormones at sites away from the thyroid glands. Drug-induced thyrotoxicosis is
caused by the interaction of the thyroid glands with certain drugs, causing
stimulation of thyroid hormone production. Excessive thyroid hormone ingestion
caused either by intentional or accidental intake will bring about thyrotoxicosis.
The most common underlying cause of hyperthyroidism in cases of thyroid storm is
Graves disease (85% of all hyperthyroidism cases in the U.S.). It is caused by the
thyrotropin receptor antibodies that stimulate excess and uncontrolled thyroidal
synthesis and secretion of thyroid hormones. It occurs most frequently in young
women (10 times more common in women compared with men) at any age group.3
Toxic multinodular goiter is the second most common group in which thyroid storm
tend to occur. Rare causes of thyrotoxicosis leading to thyroid storm include
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hypersecretory thyroid carcinoma, thyrotropin-secreting pituitary adenoma, struma
ovarii, and human chorionic gonadotropinsecreting hydatidiform mole.
Pathophysiology
The pathophysiologic mechanisms underlying the shift from uncomplicated
hyperthyroidism to thyroid storm are not entirely clear. However, they involve
adrenergic hyperactivity either via increased thyroid hormone production or
increased receptor sensitivity. Many of the signs and symptoms are related to
adrenergic hyperactivity.
When there is excess of thyroid hormones, circulating T4 and T3 are taken into the
cytoplasm of cells. T4 is converted to its active form, T3, by 5'-deiodinase enzyme viadeiodination in the outer ring of the T4 molecule. Within the cytoplasm, the T3 then
exerts its effect by passing into the nucleus and binding to thyroid hormone
receptors or thyroid hormoneresponsive elements to induce gene activation and
transcription.4
The receptors receiving the hormone will stimulate changes specific
to the tissue.
Lipogenesis and lipolysis occur as thyroid hormone induces enzymes early in the
lipogenic pathway, including malic enzyme, glucose-6-phosphate dehydrogenase,
and fatty acid synthetase.
Increased cholesterol production occurs via transcription of 3-hydroxy-3-
methylglutaryl coenzyme A reductase. Nevertheless, thyroid hormones also cause
increased excretion of cholesterol in the bile, generally resulting in a decrease in
total cholesterol. In the pituitary gland, T3 exerts negative regulation on the
transcription of the genes for the subunit and the common subunit of TSH, resulting
in a suppressed TSH in the context of thyrotoxicosis.
During thyroid storm, precipitants such as infection, stress, myocardial infarction, or
trauma will multiply the effect of thyroid hormones via freeing of thyroid hormones
from their binding sites or increased sensitivity of the receptors in tissues via
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increase in target cell -adrenergic receptor density or postreceptor modifications in
signaling pathways.
Thyroid Storm Precipitation
The precipitants of thyroid storm are as shown in Table 224-3. The most common
precipitating cause of thyroid storm currently is infection.5
Other causes include
diabetic ketoacidosis, hypoglycemia, hyperosmolar coma, radioactive iodide
treatment, pulmonary embolism, thyroid hormone overdose, withdrawal of
antithyroid medications, iodinated contrast medium ingestion, vascular accidents,
surgery, stress, parturition, eclampsia, trauma, and myocardial infarct. In
approximately 20% to 25% of cases, no acute precipitant is identified.
Table 224-3 Precipitants of Thyroid Storm
Systemic insult Cardiovascular insult
Infection Myocardial infarction
Trauma Cerebrovascular accidents
General surgery Pulmonary embolism
Hyperosmolar coma Obstetrics-related
Endocrinal insult Parturition
Diabetic ketoacidosis Eclampsia
Drug- or hormone-related Unknown etiology in up to 25% of cases
Withdrawal of thyroid medication
Iodine administration
Thyroid gland palpation
Ingestion of thyroid hormone
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Clinical Features
History and Comorbidities
The patient may only complain of constitutional symptoms such as generalized
weakness and fatigue. Heat intolerance, diaphoresis, fever, weight loss, anxiety,
emotional lability, palpitations, diarrhea, and hair loss are common historical
features. Medications that can precipitate thyrotoxicosis include iodine-containing
medications, including radiographic contrast material, amiodarone, or large doses of
topical povidone-iodine (especially if there is skin break). If there is a history of
hyperthyroidism, treatment and compliance with medication should be determined.
Physical Examination
In general, patients often appear toxic and agitated. The signs and symptoms of
hyperthyroidism patients are as shown in Table 224-4.
Table 224-4 Symptoms and Signs of Thyrotoxicosis
Affected System Symptoms Signs
Constitutional Lethargy Diaphoresis
Weakness Fever
Heat intolerance Weight loss
Neuropsychiatric Emotional lability Fine tremor
Anxiety Muscle wasting
Confusion Hyperreflexia
Coma Periodic paralysis
Psychosis
Ophthalmologic Diplopia Lid lag
Eye irritation Dry eyes
Exophthalmos
Ophthalmoplegia
Conjunctival infection
Endocrine: thyroid gland (Figure 224-1) Neck fullness Thyroid enlargement
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Tenderness Bruit
Cardiorespiratory Dyspnea Widened pulse pressure
Palpitations Systolic hypertension
Chest pain Sinus tachycardia
Atrial fibrillation or flutterCongestive heart failure
GI Diarrhea Hyperactive bowel sound
Reproductive Oligomenorrhea Gynecomastia
Decreased libido Telangiectasia
Gynecologic Menorrhagia Sparse pubic hair
Irregularity
Hematologic Pale skin Anemia
Leukocytosis
Dermatologic Hair loss Pretibial myxedema
Warm, moist skin
Palmar erythema
Onycholysis
As for thyroid storm, the additional signs and symptoms apart from those evident in
hyperthyroidism are as shown below:
Presenting Signs and Symptoms of Thyroid Storm:
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Fever is often present in thyroid storm and may be quite high. It may herald the
onset of thyrotoxic crisis in previously uncomplicated disease. Palpitations,
tachycardia, and dyspnea are common. A pleuropericardial rub may be heard. The
direct inotropic and chronotropic effects of thyroid hormone on the heart cause
decreased systemic vascular resistance, increased blood volume, increased
contractility, and increased cardiac output. Enhanced contractility produces
elevations in systolic blood pressure and pulse pressure, leading to a dicrotic or
water-hammer pulse. Atrial fibrillation occurs in 10% to 35% of thyrotoxicosis
cases.6,7
Exophthalmos is present in Graves disease. The severity of ophthalmopathy does not
necessarily parallel the magnitude of thyroid dysfunction but reflects the responsible
autoimmune process.
Not all hyperthyroidism patients present with goiter. A goiter is not present with
exogenous administration of thyroid hormone and apathetic thyrotoxicosis.
Likewise, the presence of a goiter does not necessarily confirm the diagnosis of
thyrotoxicosis. Thyroid gland tenderness can be found in inflammatory conditions
such as subacute thyroiditis.8
Thyroid storm is a clinical diagnosis for patients with preexisting hyperthyroidism.
Fever and tachycardia are cardinal features. The differential diagnosis of thyroid
storm (as shown in Table 224-6) includes infection, sepsis, cocaine use, psychosis,
pheochromocytoma, neuroleptic malignant syndrome, and hyperthermia.
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Table 224-6 Differential Diagnosis for Thyroid Storm
Infection and sepsis
Sympathomimetic ingestion (e.g., cocaine, amphetamine, ketamine drug use)
Heat exhaustion
Heat stroke
Delirium tremens
Malignant hyperthermia
Malignant neuroleptic syndrome
Hypothalamic stroke
Pheochromocytoma
Medication withdrawal (e.g., cocaine, opioids, etc.)
Psychosis
Organophosphate poisoning
Differential Diagnosis
In an effort to standardize and objectify thyroid storm as compared with severe
thyrotoxicosis, Burch and Wartofsky have delineated a point system assessing
degrees of dysfunction in four systems: thermoregulatory, central nervous, GI, and
cardiovascular systems (Table 224-7). The point system assists in determining
whether the patient's presentation is unlikely, suggestive, or highly suggestive of
thyroid storm.
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Table 224-7 Burch and Wartofsky's Diagnostic Parameters and Scoring Points for
Thyroid Storm
Diagnostic Parameters Scoring Points
1. Thermoregulatory dysfunction
Temperature C (F)37.237.7 (9999.9) 5
37.738.3 (100100.9) 10
38.338.8 (101101.9) 15
38.939.4 (102102.9) 20
39.439.9 (103103.9) 25
40 (104.0) 30
2. Central nervous system effects
Absent 0
Mild (agitation) 10
Moderate (delirium, psychosis, extreme lethargy) 20Severe (seizures, coma) 30
3. GI-hepatic dysfunction
Absent 0
Moderate (diarrhea, nausea/vomiting, abdominal pain) 10
Severe (unexplained jaundice) 20
4. Cardiovascular dysfunction
Tachycardia (beats/min)
90109 5
110119 10
120129 15
140 25
5. Congestive heart failure
Absent 0
Mild (pedal edema) 5
Moderate (bibasilar rales) 10
Severe (pulmonary edema) 15
6. Atrial fibrillation
Absent 0
Present 10
Scoring system:
Score of 45 : Highly suggestive of thyroid storm.
Score of 2544 : Suggestive of impending storm.
Score of
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Laboratory Evaluation
Serum Thyroid-Stimulating Hormone Level
In primaryhyperthyroidism, the TSH level is low as a result of the negative feedback
mechanism of a high thyroid hormone level. Nevertheless, a low TSH level by itself is
not diagnostic, as serum TSH may be reduced as a result of chronic liver or renal
disease, or the effect of certain drugs like glucocorticoids, which reduce TSH
secretion.
In secondary hyperthyroidism, TSH is increased because of increased production in
the pituitary.
Free Thyroid Hormone Levels: Free Thyroxine and Free Triiodothyronine
A low TSH with an elevated free thyroxine (FT4) confirms thyrotoxicosis. On the other
hand, a low TSH with a normal FT4 but elevated free triiodothyronine (FT3 ) is also
diagnostic of T3 thyrotoxicosis. T3 thyrotoxicosis occurs in
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affected by conditions that affect protein binding. With the improved assays for FT 4
and FT3, there is now little indication to measure total T3 and total T4.
Thyroid Antibody Titers
If Graves disease is suspected, thyroid antibody titers (to thyroid peroxidase or
thyroglobulin) will help determine diagnosis. Thyroid-stimulating antibodies are
detected in Graves disease.
Thyroid hormone studies, complete blood count, electrolytes, glucose, and renal and
liver function tests should be considered to identify comorbid abnormalities, but
treatment has to start upon suspicion of the diagnosis. Hyperglycemia tends to occur
because of a catecholamine-induced inhibition of insulin release, and increasedglycogenolysis and rapid intestinal absorption of glucose.
Mild hypercalcemia and elevated alkaline phosphatase can occur because of
hemoconcentration and enhanced thyroid hormonestimulated bone resorption.9
Hyperthyroidism induces liver enzyme metabolism, causing raised liver enzymes.
A high serum cortisol value is an expected finding in thyrotoxic individuals. This
should be the normal reaction of an adrenal gland to a body under stress. The
finding of an abnormally low cortisol level in a patient with Graves disease should
raise suspicion of coincidental adrenal insufficiency.
Imaging
Chest radiograph (or chest CT without contrast when appropriate) can be done to
rule out an infectious source as a precipitant. A thyroid sonogram with Doppler flow
can be done to assess thyroid gland size, vascularity, and the presence of nodules.
Typically, a thyroid gland secreting excessive hormones would be enlarged and have
enhanced Doppler flow. On the other hand, in the setting of subacute, postpartum
thyroiditis, silent thyroiditis, or exogenous causes of hyperthyroidism, the thyroid
gland would be expected to be small with decreased Doppler flow. Nuclear medicine
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imaging with iodine-131 would reveal a greatly increased uptake of radioiodine as
early as 1 or 2 hours after administration of the agent.
ECG in Thyrotoxicosis
ECG findings in thyrotoxicosis most commonly include sinus tachycardia and atrial
fibrillation. Sinus tachycardia occurs in approximately 40% of cases.7
Atrial fibrillation
occurs in 10% to 35% of thyrotoxicosis patientswith a tendency to occur more
commonly in patients >60 years old who are more likely to have underlying
structural heart disease.7 Premature ventricular contractions and heart blocks may
be present. Atrial premature contractions and atrial flutter may also occur in
thyrotoxicosis.
Standard Treatment for Thyroid Storm
The order of therapy in treating thyroid storm is very important with regard to the
use of thionamide and iodine therapy. Inhibition of thyroid gland synthesis of new
thyroid hormone with a thionamide should be initiated before iodine therapy to
prevent the stimulation of new thyroid hormone synthesis that can occur if iodine is
given too soon.
Treatment aims are as follows:
1. Supportive care
2. Inhibition of thyroid hormone release
3. Inhibition of new hormone production
4. Peripheral -adrenergic receptor blockade
5. Preventing peripheral conversion of T4 to T3
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References
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Kloppenburg M, Dijkmans BA, Rasker JJ. Effect of therapy for thyroid dysfunction on
musculoskeletal symptoms. Clin Rheumatol. 1993;12:341.
Lacks S, Jacobs RP. Acromegalic arthropathy: a reversible rheumatic disease.J
Rheumatol. 1986;13:634. (Case report and general review.
Lockshin M. Endocrine origins of rheumatic disease. Diagnostic clues to interrelated
syndromes. Postgrad Med. 2002;111:87. (Overview for primary care clinicians).
McGuire JL. The endocrine system and connective tissue disorders. BullRheum Dis.
1990;39:1. (A somewhat dated, but more detailed review of the subject published by
the Arthritis Foundation).