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Case 5
30-year-old female with palpitations - Ms. Waters
Author: Katherine Margo, MD; University of Pennsylvania
Learning Objectives:
1. Create a differential diagnosis of palpitations.
2. Describe the common presentations of hyperthyroidism.
3. Demonstrate the common physical findings in hyperthyroidism: Lid lag,
tremor, and hyperreflexia.
4. List the common causes of hyperthyroidism.
5. Explain the initial evaluation of a patient with suspected hyperthyroidism.
6. Discuss the usual course of a patient with Graves' disease after radioactive
iodine (RAI) treatment.
7. Discuss the treatment of hypothyroidism after RAI treatment.
Summary of Clinical Scenario: Ms. Waters is a 30-year-old woman who
presents with her partner to the clinic after several weeks of palpitations
associated with mild dyspnea, increased sweating, and some exercise intolerance.
She has also noticed weight loss, light periods, and loose stools. Exam reveals
tachycardia, lid lag, hyperreflexia of deep tendon reflexes, two beats of ankle
clonus, and fine tremor. After careful consideration of the differential diagnosis,
electrocardiogram (ECG), thyroid stimulating hormone (TSH), thyroxine (T4), and
complete blood count are obtained. The results confirm a diagnosis of
hyperthyroidism. The patient is given propranolol for adrenergic symptoms and
sent for a radioactive iodine uptake scan. Diffuse increased radioactive iodine
uptake despite low TSH confirms the diagnosis of Graves disease. After being
educated about her treatment options, the patient chooses to take radioactive
iodine and is followed for several months until she returns with hypothyroid
symptoms, which are also treated.

Dyspnea

Key Findings from History

Increased sweating
Light periods
Loose stools

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No caffeine, alcohol, or drugs

Stress

Weight loss
Lid Lag
Thyroid enlargement

Key Findings from Physical

Exam

Systolic murmur
Hyperreflexia
Clonus
Tremor

Cardiac dysrhythmias
Anxiety / panic disorder

Differential Diagnosis

Anemia
Hyperthyroidism
Drug / caffeine abuse

TSH: <.01 mIU/L (low)

T4 (thyroxine): 15 mcg/dL (high)
ECG: Normal

Key findings from Testing

Radioactive iodine uptake (RAIU)

test and scan: Diffuse increased
uptake in the thyroid gland

Final Diagnosis

Hyperthyroidism

Case Highlights: Students review the hypothalamic-pituitary axis and gain an

improved understanding of the endocrine pathophysiology underlying the
interpretation of blood tests and treatment of thyroid disorders. Short video clips
review proper technique for thyroid and deep tendon reflex exams. Students also
learn how to interpret results of a radioactive iodine uptake test and scan.

Key Teaching Points

Knowledge:
Common causes of palpitations:

Hyperthyroidism
Cardiac

Arrhythmias
Cardiomyopathy

Symptoms: Hyperthyroidism presents with multiple symptoms that vary

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according to the age of the patient, the duration of the illness, the magnitude of
hormone excess, and presence of comorbid conditions. Symptoms are related to
the thyroid hormone's stimulation of catabolism, and enhancement of sensitivity
to catecholamines.

Signs and Symptoms of Hyperthyroidism

in Younger vs. Older Patients
Patients < 50 years

Patients > 70 years

Tachycardia (96%)

Tachycardia (71%)

Fatigue (84%)

Fatigue (56%)

Weight loss (50%)

Heat intolerance (92%)
Tremor (84%)
Increased sweating (96%)
Depression
Hyperreflexia
Diarrhea

Weight loss
Atrial fibrillation
Many other typical symptoms
of hyperthyroidism are absent
in patients older than 70

Light periods

Symptoms are related to the thyroid hormone's stimulation of catabolism

(unchecked by pituitary modulation) and enhancement of sensitivity to
catecholamines:
Increased heart rate and cardiac output due to:
Increased peripheral oxygen needs
Increased cardiac contractility
Weight loss due to:
Increased calorigenesis (heat produced by consumption of food)
Increased gut motility and the associated hyperdefecation and
malabsorption.
Exercise intolerance and fatigue contributed to by:
Oxygen consumption and CO2 production
Respiratory muscle weakness

Pathophysiology:

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The hypothalamus releases thyrotropin releasing hormone (TRH), which

stimulates the anterior pituitary gland to produce and release thyroid
stimulating hormone (TSH). TSH, in turn, stimulates the thyroid gland to
make thyroid hormone (T3 and T4). Thyroid hormone exerts negative
feedback control over the hypothalamus as well as the anterior pituitary,
thus controlling the release of both TRH from hypothalamus and TSH from
anterior pituitary gland.
Increased levels of circulating thyroid hormones (hyperthyroidism) result in
negative feedback and a decreased level of TSH.
Conversely, decreased levels of circulating thyroid hormones result in an
increased level of TSH.
Etiology:
1. Toxic diffuse goiter (Graves' disease)
Causes majority (6080%) of hyperthyroidism
Autoimmune disease caused by an antibody that acts at the TSH receptor
and stimulates the gland to synthesize and secrete excess thyroid hormone
Females 510 times more likely to have it than males
Age of peak incidence: 4060 years

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Associated with family history of thyroid disease and other autoimmune

diseases
Triggers: Stressful life events, high iodine intake, recent pregnancy
Hypervascularity of the thyroid may result in a bruit or thrill upon
auscultation that is not present in other etiologies of hyperthyroidism
Pretibial myxedema, a rare finding, is most common in Graves' disease and
is caused by the deposition of hyaluronic acid in the dermis and subcutis.
Ophthalmopathy:
Exopthalmus or proptosis: Forward projection or bulging of the eye
out of the orbit, most commonly seen in Graves disease. Can be
either bilateral or unilateral.
While 50% of patients with Graves' have some eye involvement by
MRI, only about 2030% of these are clinically relevant.
Up to 10% of the eye manifestations can happen when the patient is
euthyroid or even hypothyroid.
Treatment of hyperthyroidism does not affect the eye manifestations.
In fact, eye symptoms may progress in some patients treated with
radioactive iodine
2. Toxic nodular goiter
Causes about 5% of cases of hyperthyroidism.
Thyroid nodules are common, but most are not symptomatic, and only
45% are cancerous.
Thyroid nodules are more common in patients over 40. These older patients
more often have multinodular disease, whereas solitary nodules are seen
more often in younger patients and can be associated with iodine deficiency.
3. Thyroiditis
Disease in which thyroid hormone leaks from an inflamed thyroid, typically
short-term. May happen after a viral illness or pregnancy.
4. Excessive iodine
May occur through diet or a medication such as amiodarone, which can
induce thyroiditis but also has high iodine content.
Causes of goiter (enlarged thyroid gland): An enlarged thyroid can be seen in
patients with too much, normal amounts, or not enough thyroid hormone.
Lack of iodine Worldwide, the most common cause of goiter (as well as
mental retardation). Most affected areas are Northern Africa and Pakistan,
but parts of Europe also have mildly low iodine levels. Iodized salt is the
easiest and least expensive way to supplement iodine.
Hashimoto's disease (cause of hypothyroidism)
Graves' disease (cause of hyperthyroidism)
Nodules (single or multiple): Gland feels irregular.
Thyroid cancer Thyroid gland is enlarged and nodular.

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Pregnancy May occasionally cause slight enlargement of the thyroid gland.

Thyroiditis (inflammation of the thyroid): Enlarged, often tender, thyroid
gland.
Hypothyroidism
Symptoms: The following symptoms of hypothyroidism result from metabolic
slowing (opposite of hyperthyroidism):
Weight gain
Cold intolerance
Pedal edema
Heavy periods
Fatigue (common in both hyper and hypothyroidism)

Skills
Physical exam:
Thyroid exam:
1. Locate the thyroid gland using the thyroid cartilage as a landmark and
moving the sternocleidomastoid muscle out of the way.
2. Have patient take a sip of water, as swallowing elevates the thyroid and
eases palpation.
3. Use your left hand to fix the gland in place while your right hand palpates
the right lobe, and vice versa.
4. Note tenderness, size, and presence of nodules.
Deep tendon reflexes (DTRs): Always compare each reflex immediately with its
contralateral counterpart so you detect any asymmetries:
Biceps reflex: Use your finger to identify the biceps brachii tendon and tap
over that finger with the reflex hammer.
Triceps reflex: Hang patients forearm loose at a right angle to place the
triceps brachii tendon under gentle tension to elicit reflex and tap tendon
with the reflex hammer.
Patellar reflex: Have patient dangle his legs off of the examination table
and strike the patellar tendon just below the patella with the reflex hammer.
Ankle reflex: Apply gentle dorsiflexion while tapping Achilles tendon with
the reflex hammer.
If reflexes are difficult to elicit, increase tone by having patient pull clenched
hands apart or clenching his teeth.
Other neurological findings:
Ankle clonus: Elicited by rapidly dorsiflexing the foot, causing alternate
contraction and relaxation of the gastrocnemius and soleus muscles.
Tremor: Elicited by having patient stretch out his arms and close his eyes.

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Lid lag: This may be elicited by asking the patient to follow with his eyes
your finger moving slowly from her upper to lower field of vision. In lid lag,
the upper eyelid lags behind the upper edge of the iris as the eye moves
downward. Be careful when performing this maneuver, if the object (your
finger) is moved too quickly, the diagnosis may be missed.

Differential diagnosis:
1. Cardiac arrhythmias: Commonly cause palpitations, particularly when the
heartbeat is fast, though most people with arrhythmias do not notice
palpitations. Symptoms, when present, can be palpitations from rapid or
irregular heartbeat, lightheadedness, chest pain, and shortness of breath.
Some arrhythmias, like paroxysmal supraventricular tachycardia, are more
common in young people. Stress can cause arrhythmias due to adrenergic
overdrive.
2. Anxiety and panic disorder: Commonly cause palpitations and shortness
of breath. May be difficult to distinguish anxiety from hyperthyroidism, as
tachycardia, tremulousness, irritability, weakness, and fatigue are common
to both disorders. In anxiety, however, the peripheral manifestations of
excess thyroid hormones are absent; the skin is usually cold and clammy
rather than warm and moist. In anxious patients, weight loss usually occurs
due to anorexia as opposed to the increased appetite seen in
hyperthyroidism. Furthermore, panic attacks are distinct episodes of fear
and panic triggered by a particular place or event, or for no apparent
reason. A reasonable screening test for panic disorder is to ask, Have you
experienced brief periods, for seconds or minutes, of an overwhelming panic
or terror that was accompanied by racing heartbeats, shortness of breath,
or dizziness? Patients often underestimate how much stress they are under
and how much it can affect them. Especially in the setting of high stress,
palpitations are likely to be due to anxiety or panic disorder. In one
prospective study of 190 patients at a university medical center, 31% of
palpitations were due to anxiety or panic disorder.
3. Anemia: May cause palpitations because of tachycardia from hypovolemia.
The heart responds to low blood volume by speeding up to increase the
exposure of the blood to oxygenation in the lungs. Anemia can cause
dyspnea on exertion because of the lack of oxygen carrying capacity of the
blood. A common source of anemia in menstruating women is heavy
periods. It is unusual in young people to be losing blood from other sites
without obvious trauma. If the anemia is caused by a nutritional deficiency
(iron, vitamin B12 or folate), it may also be associated with weight loss.
4. Hyperthyroidism: Palpitations caused by tachycardia. The increase in
thyroid hormone increases the metabolism, including heart rate. In
hyperthyroidism, weight loss occurs despite increased appetite. Other
effects of hyperthyroidism are loose stools, hyperdefecation, light periods,
and sleep disturbance.
5. Drug/caffeine abuse: Most patients tell the truth about caffeine use,
though it is important to consider sources other than coffee and tea, such as

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many sodas. Street drugs, such as cocaine and even alcohol, can also cause
tachycardia. Caffeine and other drugs that cause palpitations (e.g.,
amphetamines, dextroamphetamines) can also cause weight loss. A high
index of suspicion should be maintained if someone has no other obvious
cause of palpitations and has other signs such as dilated pupils, increased
energy, increased blood pressure, and unusual behavior. Most people who
use cocaine would be unlikely to present to a physician office in this
manner.
Less likely diagnoses:
Dehydration causing hypovolemia can cause tachycardia. Usually an acute
presentation. Also associated with orthostatic symptoms, such as dizziness.
Although aortic stenosis has been known to cause palpitations and, most
ominously, syncope, it is usually associated with chest pain or dizziness.

Studies:
Thyroid Stimulating Hormone (TSH)
Increased levels of TSH = hypothyroid
Decreased levels of TSH = hyperthyroid
Thyroid hormone (thyroxine, or T4): While TSH level is usually sufficient to
diagnose either hypo- or hyperthyroidism, if pituitary pathology is interfering with
the feedback cycle, TSH may not accurately reflect the levels of circulating thyroid
hormone, and drawing a T4 level will help in the investigation.
Utility of TSH and T4 in evaluation of suspected thyroid disease
TSH

Serum Free T4

Condition indicated

Increased

Decreased

Hypothyroidism

Mildly elevated
(5-10 mIU/L)

Normal

Subclinical hypothyroidism

Inappropriately
normal

Increased

Pituitary adenoma
(TSH-producing) or thyroid
hormone resistance

Decreased

Increased

Thyrotoxicosis
(hyperthyroidism)

TSH decreased
(may occasionally
be normal or
slightly elevated)

Decreased

Central (or pituitary)

hypothyroidism (TSH
and/or TRH deficiency)

TSH decreased

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Serum Free T4 T3, Toxicosis

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Serum T3
Increased

Electrocardiogram (ECG): Rule out cardiac pathology and arrhythmias.

Complete blood count (CBC): Rule out anemia that could account for
tachycardia and palpitations.
Radioactive iodine uptake (RAIU) test and scan: This nuclear medicine test
measures the amount of radioactive iodine taken up by the thyroid in 24 hours,
after a set dose is ingested. Interpretation is made by comparing to normal
uptake (1530%):
High RAIU (>30%)

Low RAIU (<15%)

Graves disease: Increased creation

of thyroid hormone results in
increased radioactive iodine uptake
used to synthesize the thyroid
hormone (diffuse pattern on RAIU
scan).

Sub-acute thyroiditis: Gland

leaking excess hormone, so
radioactive iodine uptake is
low in this case, as more
thyroid hormone is not
synthesized.

Multi-nodular goiter (nodular

pattern)

Silent thyroiditis

Toxic solitary nodule (nodular

pattern)

Iodine induced

TRH-secreting pituitary tumor

Exogenous L-Thyroxine

HCG-secreting tumor

Struma ovarii
Amiodarone

Thyroid ultrasound: Used in the evaluation of thyroid nodules and thyroid

enlargement. Ultrasound characteristics of a nodule can be used to stratify risk of
malignancy and ultrasound can guide the fine needle aspiration of nodules that
are not easily palpated. Ultrasound is starting to be used to differentiate Graves
disease from other causes of hyperthyroidism when RAI scanning is not available
or is contraindicated. Some experts predict that color-flow Doppler ultrasound
may replace RAI scanning since it has similar accuracy but is safer, less costly and
easier to administer.
Thyroid antibodies: Thyroid peroxidase antibodies are present in 7080% of
Graves' patients. These and TSH receptor antibodies can differentiate Graves'
disease from toxic nodular goiter. Some experts feel that these antibody tests can
be done instead of a thyroid scan provided that silent thyroiditis can be ruled out
clinically.

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Management:
Hyperthyroidism:
Propranolol, a beta-blocker, can be used for symptomatic relief of adrenergic
symptoms (tachycardia, tremor, heat intolerance).
Patients diagnosed with Graves disease should be referred to an
ophthalmologist.
Medications:
Block thyroid gland from making more thyroid hormone
Side effects: Minimal, but low white blood cell count in < 1% of patients
Clinical improvement usually seen after one month, but three months before
thyroid level decreases
Treatment duration: Several years (> 50% of patients become hyperthyroid
when they cease medications)
Requires regular blood monitoring to keep dose optimal. Symptoms and
dose may fluctuate
May try this option initially and switch to radioactive iodine later.
Oral radioactive iodine (single dose):
Side effects: Transient (a few days) soreness of the neck or brief worsening
of symptoms. People with ophthalmopathy may experience worsening of
symptoms.
Over a few months the radioactive iodine destroys many of the overactive
thyroid cells, so that the level of thyroid hormone in the blood decreases.
Occasionally a second dose may be needed.
Eventually many patients become hypothyroid and need to take small doses
of replacement thyroid hormone.
Fewer European patients choose radioactive iodine compared to the U.S.,
where > 70% of patients choose this treatment.
Obtain pregnancy test prior to initiating radioactive iodine treatment. Also,
patient should not be near pregnant women or young children for several
days. Exposure of fetus or young child to radioactive iodine could result in
deleterious effect on their thyroid.
May be able to discontinue propranolol in a few months.
Check TSH every two to three months until it has stabilized and every six or
so months thereafter.
Expect patient to become hypothyroid at some point. Alert them to
symptoms of hypothyroidism in advance, so they can be tested earlier if
need be.
Surgery:
Not usually recommended as first-line therapy
Hypothyroidism:
Hypothyroidism is easier to manage than hyperthyroidism once the correct dose

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of synthetic hormone (levothyroxine) has been established (where patient feels

normal and TSH is in normal range). Can be managed with one or two blood tests
a year, and dose usually stays about the same.
Levothyroxine
Increase dose slowly, especially in elderly or mildly hypothyroid patients.
Aim for dose of 1.51.8 mcg per kilogram.
Check TSH level one month after starting.
In primary hypothyroidism, once a stable TSH level has been achieved,
blood work may be checked annually.
In secondary hypothyroidism (due to radioactive iodine treatment) amount
of destroyed thyroid is unknown. Must monitor closely until levels stabilize.
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