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Case 5

30-year-old female with palpitations - Ms. Waters

Author:Katherine Margo, MD; University of Pennsylvania

Learning Objectives:

Create a differential diagnosis of palpitations.1.Describe the common presentations of hyperthyroidism.2.

Demonstrate the common physical findings in hyperthyroidism: Lid lag,

tremor, and hyperreflexia.

3.

List the common causes of hyperthyroidism.4.

Explain the initial evaluation of a patient with suspected hyperthyroidism.5.

Discuss the usual course of a patient with Graves' disease after radioactive

iodine (RAI) treatment.

6.

Discuss the treatment of hypothyroidism after RAI treatment.7.

Summary of Clinical Scenario:Ms. Waters is a 30-year-old woman who

presents with her partner to the clinic after several weeks of palpitationsassociated 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 hypothyroidsymptoms, which are also treated.

Key Findings from History

Dyspnea

Increased sweating

Light periods

Loose stools

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No caffeine, alcohol, or drugs

Stress

Key Findings from PhysicalExam

Weight loss

Lid Lag

Thyroid enlargement

Systolic murmur

Hyperreflexia

Clonus

Tremor

Differential Diagnosis

Cardiac dysrhythmias

Anxiety / panic disorder

Anemia

Hyperthyroidism

Drug / caffeine abuse

Key findings from Testing

TSH:

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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 Hyperthyroidismin 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

Light periods

Weight loss

Atrial fibrillation

Many other typical symptomsof hyperthyroidism are absent

in patients older than 70

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 contractilityWeight 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:

Toxic diffuse goiter(Graves' disease)1.

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

Toxic nodular goiter2.

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.

Thyroiditis3.

Disease in which thyroid hormone leaks from an inflamed thyroid, typically

short-term. May happen after a viral illness or pregnancy.

Excessive iodine4.

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 iodineWorldwide, 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 cancerThyroid gland is enlarged and nodular.


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PregnancyMay 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:

Locate the thyroid gland using the thyroid cartilage as a landmark and

moving the sternocleidomastoid muscle out of the way.

1.

Have patient take a sip of water, as swallowing elevates the thyroid and

eases palpation.

2.

Use your left hand to fix the gland in place while your right hand palpates

the right lobe, and vice versa.

3.

Note tenderness, size, and presence of nodules.4.

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 clenchedhands 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: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.

1.

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 commonto 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.

2.

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.

3.

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.

4.

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

5.


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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 T4in evaluation of suspected thyroid disease

TSH Serum Free T4 Condition indicated

Increased Decreased Hypothyroidism

Mildly elevated

(5-10 mIU/L)Normal Subclinical hypothyroidism

Inappropriately

normalIncreased

Pituitary adenoma

(TSH-producing) or thyroid

hormone resistance

Decreased IncreasedThyrotoxicosis

(hyperthyroidism)

TSH decreased

(may occasionally

be normal or

slightly elevated)

Decreased

Central (or pituitary)

hypothyroidism (TSH

and/or TRH deficiency)

TSH decreased Serum Free T4

Normal

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 (

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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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