Download File - Endocrine Health

Hyperthyroidism: Walking
the Thyroid Tightrope
Jamie Shelly, PharmD
PGY1 Community Pharmacy Resident
UNC Eshelman School of Pharmacy/Kerr Drug
May 15, 2012
I have no relationships with commercial interests
related to the content of this presentation.
1.
Describe the etiology and pathophysiology of
hyperthyroidism
2.
Identify symptoms associated with hyperthyroidism
3.
Explain the use of non-pharmacologic,
pharmacologic, and adjunctive treatment strategies
in patients with hyperthyroidism
4.
Given patient cases, formulate appropriate
recommendations and counseling for patients with
hyperthyroidism
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http://www.differencebetween.net/wp-content/uploads/2009/12/thyroid-system.jpg
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Cause
Mechanism
Graves’ disease
Antithyroid antibodies stimulate thyroid to
synthesize and secrete excess thyroid hormone
Toxic multinodular goiter
(TMNG) aka Plummer’s
disease
Iodine deficiency; leads to autonomous thyroid
hormone production
Thyroiditis
Viral, postpartum, lymphocytic, medicationinduced; causes hormone to leak from gland
Toxic adenoma (TA)
Benign thyroid hormone-secreting tumor; iodine
deficiency
Iodine-induced
Amiodarone, radiographic contrast, excessive
iodide ingestion; increases synthesis and release of
thyroid hormones
Factitious hyperthyroidism
Excessive exogenous thyroid hormone intake
Secondary hyperthyroidism
Excessive pituitary thyroid-stimulating hormone
Am Fam Physician. 2005;72(4):623-30.
J Fam Pract. 2011;60(7):388-95.
Drug
Mechanism(s)
Timing of onset
Amiodarone
Iodine induced (type 1)
Thyroiditis (type 2)
Months to years
Often >1 year
Lithium
Painless thyroiditis
Often >1 year
Interferon α
Painless thyroiditis; Graves’
disease
Months
Interleukin-2
Painless thyroiditis; Graves’
disease
Months
Iodinated contrast
Underlying thyroid autonomy
Weeks to months
Radioactive iodine,
early
Destruction
1-4 weeks
Radioactive iodine for
TMNG, late
Graves’ disease
3-6 months
Endocr Pract. 2011;17(3):456-520.
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http://www.beltina.org/pics/graves_ophthalmopathy.jpg
https://www.nursingunlimited.com/Online_Classes/Courses/Graves_Disease/Graves_Disease_page1_clip_image008.jpg
http://dermimages.med.jhmi.edu/images
/colloid_goiter_2_080613.jpg
http://2.bp.blogspot.com/LpOZUA9RZVw/Tjg9HPGOOPI/AAAAAAAAAg/47E8HlqpP9M/s1600/goiter.png
http://www.thyroidimaging.com/gozzo_5.jpg
Which of the following symptoms is NOT
typically associated with hyperthyroidism?
a.
b.
c.
d.
Increased heart rate
Decreased appetite
Increased irritability
Decreased heat tolerance

Thyroid hormones influence nearly every tissue and
organ system in the body
 Increasebasal metabolic rate and thermogenesis
 Decreaseserum cholesterol and systemic vascular
resistance

Therefore, untreated hyperthyroidism can cause:





Weight loss
Osteoporosis
Embolic events
Atrial fibrillation
Cardiovascular collapse/death
Circulation. 2007;116:1725-35.
Endocrinol Metab Clin North Am. 1993; 22:263-77.
Acta Endocrinol. 1993;128:230-34.
Surgical intervention
Radioactive iodine (RAI)
Antithyroid drugs (ATD)
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Advantages


Rapid
Effective, especially in
patients with large
goiters
Disadvantages






http://www.bloggingjunction.com/wpcontent/uploads/2010/11/Advantages-And-Disadvantages.jpg
Most invasive option
Most costly
Pain
Scarring
Permanent
hypothyroidism
Potential for
complications (e.g.
laryngeal nerve damage,
hypoparathyroidism)
Lancet. 2003;362:459-68.
Reserved for certain situations:
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
Intolerance or poor
response to antithyroid
drugs

Pediatric patients with
severe disease

Refusal to undergo
radioactive iodine therapy


Presence of very large
goiter (compressive
symptoms or cosmetic
reasons)
Patients requiring
immediate normalization
of thyroid functions

Presence of clinically
suspicious or potentially
malignant thyroid nodule

Pregnancy
Am Fam Physician. 2005;72(4):623-30.
J Fam Pract. 2011;60(7):388-95.
Advantages


Cures hyperthyroidism
Most cost effective
Disadvantages





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Permanent
hypothyroidism is almost
inevitable
May worsen
ophthalmopathy
Pregnancy must be
deferred 6-12 months
No breast-feeding
Potential risk of
hyperthyroidism
exacerbation
Lancet. 2003;362:459-68.

Concentrates in thyroid gland and destroys
tissue

Generally requires a single dose
 Up to 20% of patients require a second dose, given
~6-12 months after first dose

Thyroid function returns to normal 2-6 months
after treatment
 Hypothyroidism usually develops within 4-12 months
Am Fam Physician. 2005;72(4):623-30.
Thyroid. 1998;8:653–59.
Advantages
Noninvasive
Lower initial cost
Low risk of
hypothyroidism
 Possible remissions



Disadvantages



Low cure rate
Adverse drug reactions
Compliance
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Lancet. 2003;362:459-68.

Inhibit thyroid hormone synthesis
http://doctorsgates.blogspot.com/2010_12_13_archive.html

Goal of treatment is to render the patient
euthyroid as quickly and safely as possible

Can be used as:
 Primary treatment
▪ Usually given for 6-18 months
 Adjunctive therapy
▪ Before RAI or surgery
▪ After RAI or surgery if hyperthyroidism recurs
Am Fam Physician. 2005;72(4):623-30.
Imidazoles
Methimazole
[Tapazole]
(MMI)
Thiouracils
Carbimazole
-Available only in Europe
-Metabolized to methimazole
immediately following ingestion
Propylthiouracil
(PTU)
Lancet. 2003;362:459-68.

Generally drug of choice
 Compared to PTU:
▪ Lower cost
▪ Longer half life (6-8 hours vs. 1-2 hours for PTU)
▪ Fewer adverse effects

Starting dose=15-30 mg PO daily

Maintenance dose=5-10 mg per day
Am Fam Physician. 2005;72(4):623-30.

At higher doses, blocks peripheral conversion
of thyroxine (T4) to triiodothyronine (T3)

Preferred for pregnant women

Starting dose=100 mg PO TID

Maintenance dose=100-200 mg per day
Am Fam Physician. 2005;72(4):623-30.
Study Design
Objective
Prospective, randomized controlled trial
Compare methimazole vs. propylthiouracil
in terms of efficacy and adverse reactions
Participants
303 with newly diagnosed, untreated
hyperthyroidism due to Graves’ disease
Methods
Patients received either MMI 15 mg/day,
MMI 30 mg/day, or PTU 300 mg/day
Free T4 (FT4), free T3 (FT3), and frequency
of adverse effects measured at 4, 8, and 12
weeks
J Clin Endocrinol Metab. 2007;92(6):2157-62.
Efficacy MMI 30 mg/d achieved normal thyroid levels in more
Results patients than PTU 300 mg/d and MMI 15 mg/d (96.5%
vs. 78.3%; p=0.001; and 86.2%, p=0.023, respectively)
When divided into two groups based on initial severity:
No statistically significant difference in achieving
euthyroidism between MMI 15 mg/d and 30 mg/d in
patients with mild-to-moderate Graves’
In patients with severe hyperthyroidism, MMI 30 mg/d
was more effective than PTU 300 mg/d and MMI 15
mg/d (p=<o.o5)
J Clin Endocrinol Metab. 2007;92(6):2157-62.
Safety
Results
Adverse effects were experienced by more than half
of patients receiving PTU
•26.9% of patients on PTU showed AST and ALT
more than double the upper range of normal vs.
6.6% of those receiving MMI 30 mg/d (p<0.001)
Frequency of adverse effects significantly lower with
MMI 15 mg/d vs. 30 mg/d
Conclusion Use MMI 15 mg/day in patients with mild-tomoderate Graves’ and MMI 30 mg/day in severe
Graves’
PTU not recommended as initial ATD
J Clin Endocrinol Metab. 2007;92(6):2157-62.
Minor
 Rash, fever, gastrointestinal upset, arthralgias
Severe
 Agranulocytosis
 Most serious complication of ATD
 Patients should be notified to discontinue ATDs
immediately if they develop a fever or sore throat

Liver damage
 Patients should be notified to discontinue ATDs if
jaundice, dark urine, malaise or light-colored stools
develop
Lancet. 2003;362:459-68.
Study Design
Retrospective, mono-centered
Objective
Determine if prevalence of agranulocytosis
differs based on starting dose of MMI in
patients with Graves’
Methods
Compared prevalence of agranulocytosis
in patients receiving MMI 30 mg/d vs. 15
mg/d who were observed for at least one
year
Participants
Newly diagnosed with Graves’ disease
2739 subjects treated with MMI 15 mg/d
2087 subjects treated with MMI 30 mg/d
Thyroid. 2009;19(6):559-63.
Results
Conclusion
“MMI-induced agranulocytosis is more likely to occur
with a larger dosage of MMI. We recommend 15 mg/d
of MMI as the initial treatment dose for Graves’
disease.”
Thyroid. 2009;19(6):559-63.
A new physician calls your pharmacy requesting a
methimazole starting dose for a patient newly diagnosed
with severe Graves’ disease. He has not yet seen a patient
with Graves’ and wonders whether it will be best to start
the patient on 15 mg or 30 mg daily. Which would you
recommend and why?
a. 15 mg/day; is associated with fewer serious side
effects than 30 mg/day
b. 15 mg/day; is as efficacious as 30 mg/day in severe
Graves’ disease
c. 30 mg/day; is more efficacious than 15 mg/day in
severe Graves’ disease
d. 30 mg/day; is recommended starting dose in Graves’
disease of any severity

Thyroid function should be assessed every
4-6 weeks for the first 4-6 months

Doses are adjusted based on clinical status
and free T4 and T3 levels

TSH may remain low or undetectable for
months after a patient becomes euthyroid
 Therefore, TSH should NOT be used to monitor
therapy
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b5d0d836631ab61bc587adc214.jpg
Lancet. 2003;362:459-68.

Can occur in up to 50% of patients who respond
initially
 Regardless of regimen used

More likely in patients who:
 Smoke
 Have large goiters
 Have elevated thyroid-stimulating antibody levels at
the end of therapy

If relapse occurs, RAI or surgery is
recommended, although ATD therapy can be
restarted
Arch Intern Med. 2000;160:1067-71.
Eur J Endocrinol. 2002;147:583-9.

Relieve adrenergic symptoms (e.g. tremor, heat
intolerance, palpitations, nervousness)

Propranolol used most widely
 Initial dose: 10-20 mg PO q 6 h
 Increase until symptoms are controlled
▪ Doses from 80-320 mg per day are usually sufficient

Calcium channel blockers can be used to reduce
heart rate in patients who cannot tolerate beta
blockers
Ann Surg. 2001;233:60-4.
CMAJ.2003;168:575-85.

Inhibit thyroid hormone release and block
peripheral conversion of T4 to T3

NOT used in routine treatment due to
paradoxical increases in hormone release that
may occur with prolonged use

May see used to reduce gland vascularity before
surgery for Graves’ disease and before
emergency nonthyroid surgery if beta blockers
cannot control hyperthyroidism
Arch Intern Med. 2000;160:1067-71.
Thyroid. 2001;11:561-7.
Depends on:







Cause
Severity
Comorbid conditions
Goiter size
Patient age
Patient preference
Physician preference
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Am Fam Physician. 2005;72(4):623-30.

Most recent“Hyperthyroidism and Other
Causes of Thyrotoxicosis: Management
Guidelines of the American Thyroid
Association and American Association of
Clinical Endocrinologists”
 Published in 2011

100 evidence-based recommendations
Endocr Pract. 2011;17(3):456-520.
Graves’ disease
TMNG & TA
Thyroiditis
• RAI, ATDs, or
surgery
• RAI or surgery
• Beta blockers and
NSAIDs
• Note: guidelines
differ for pts with
Graves’
ophthalmopathy
(based on disease
activity, severity,
and smoking
status)
• Prolonged ATD tx
may be best in
individuals with
limited longevity
or at increased
surgical risk
• Those failing to
respond or with
moderate-tosevere Sx should
be treated with
corticosteroids
(prednisone 40 mg
daily x 1-2 wks)
Endocr Pract. 2011;17(3):456-520.

Methimazole should be used in virtually every
patient who chooses ATDs, except:
 First trimester of pregnancy
 Thyroid storm
 Patients with minor reactions to methimazole
who refuse RAI or surgery
Endocr Pract. 2011;17(3):456-520.

Patients should be informed of ATD side effects and the
necessity of informing the physician promptly if they should
develop symptoms suggestive of agranulocytosis or hepatic
injury

Before starting ATDs and at each subsequent visit, patients
should be alerted to stop the medication immediately and
call their physician when there are symptoms suggestive of
agranulocytosis or hepatic injury
Endocr Pract. 2011;17(3):456-520.

Should be given to
 Symptomatic elderly patients
 Patients with resting heart rates above 90 bpm
 Patients with coexistent cardiovascular disease

Beta blockers should be considered in ALL
patients with symptomatic hyperthyroidism
Endocr Pract. 2011;17(3):456-520.
Study Design Prospective, randomized controlled trial
Objective
Evaluate effect of intermediate and long acting
cardio-selective β1 blockers in comparison with
the well established, nonselective β-blocker
propranolol
Participants
Untreated, newly diagnosed with
hyperthyroidism (etiology not specified)
Group 1: propranolol 60 mg daily in three divided
doses (n=15)
Group 2: atenolol 50 mg daily as a single dose
(n=15)
Group 3: metoprolol 100 mg daily in two divided
doses (n=10)
Proc West Pharmacol Soc. 2003;46:125-6.
Results
Conclusion
Degree of clinical improvement in palpitations,
excessive sweating, diarrhea, muscle weakness,
and tremor in those receiving atenolol and
metoprolol was comparable to the propranolol
group
Atenolol and metoprolol as effective as
propranolol in abolishing nervousness and
insomnia
The use of long and intermediate acting
selective β1 blockers is effective in managing
hyperthyroidism
Proc West Pharmacol Soc. 2003;46:125-6.
Drug
Dosage
Frequency
Considerations
Propranolol 10-40 mg
TID-QID
•Nonselective beta-adrenergic receptor
blockade
•Longest experience
•May block T4 to T3 conversion at high doses
•Preferred agent for nursing mothers
Atenolol
25-100
mg
QD or BID
•Relative beta -1 selectivity
•Increased compliance
Metoprolol
25-50 mg
QID
•Relative beta -1 selectivity
Nadolol
40-160
mg
QD
•Nonselective beta-adrenergic receptor
blockade
•Once daily
•Least experience to date
•May block T4 to T3 conversion at high dose
Endocr Pract. 2011;17(3):456-520.
Which patient diagnosed with hyperthyroidism
would be least likely to benefit from beta
blocker therapy?
a. 83 yom with tremor and palpitations
b. 56 yof with CHF, edema, and heat
intolerance
c. 19 yof with a heart rate of 93 bpm
d. 62 yom with goiter, weight loss, and
Graves’ ophthalmopathy

Prior to initiating ATDs, patients should have:
 Baseline CBC including white count with differential
 Liver profile

A differential WBC count should be obtained:
 During febrile illness
 At onset of pharyngitis

Routine monitoring of white blood counts is not
recommended

Following thyroidectomy:
 Serum calcium or intact parathyroid hormone
▪ Administer oral calcium and calcitriol based on results
Endocr Pract. 2011;17(3):456-520.

Occurs in 1-2% of the US population

Characterized by TSH <0.1mU/L and normal
levels of T3 and T4

Causes are similar to overt hyperthyroidism

Carries significant health risks




Atrial fibrillation
Systolic and diastolic cardiac dysfunction
Decreased bone density
Increased risk of dementia
J Fam Pract. 2011;60(7):388-95.

If subclinical hyperthyroidism is to be treated, treatment
should be based on etiology and follow the same
principles as overt hyperthyroidism
Subclinical Hyperthyroidism: When to Treat
Factor
Age >65
TSH (<0.1 mU/L)
TSH (0.1-0.5 mU/L)
Yes
Consider treating
Heart disease
Yes
Consider treating
Osteoporosis
Yes
No
Menopausal
Consider treating
Consider treating
Hyperthyroid symptoms
Yes
Consider treating
Consider treating
No
Age <65 with comorbidities
Age <65, asymptomatic
Endocr Pract. 2011;17(3):456-520.

“Clinicians should advise patients with
Graves’ disease to stop smoking and refer
them to a structured smoking cessation
program”
 Smoking is the most important known risk factor
for the development or worsening of Graves’
ophthalmopathy
▪ Risk is proportional to the number of cigarettes smoked
per day
http://www.howtostopsmokinghelp.com/
Endocr Pract. 2011;17(3):456-520.
Study Design
Meta-analysis
Objective
Examine association of smoking and thyroid
disorders
Data Sources
MEDLINE (25 studies with clinical data retrieved)
and Cochrane library (0 studies identified)
Significant
Conclusions
•Smoking increases the risk of Graves’
ophthalmopathy beyond the risk associated with
Graves’ disease alone
•Cessation of smoking is associated with a lower
risk of Graves’ disease than current smoking
•Cessation of smoking may lead to a decrease in
morbidity from Graves’ disease, especially in
women
Eur J Endocrinol 2002 ;146(2):153-61.
E.C. is a 25 year old Caucasian female with newly diagnosed
hyperthyroidism due to Graves’ disease. She is to be initiated
on treatment as soon as possible. Additional information
includes:
Medications:
 5’2’’, 107 lbs.
Sumatriptan 50mg PO prn for
migraine. May take second
 Allergies: PCN, codeine
dose 2 hours later if no
nd
 SH: 2 grade teacher,
response
denies EtOH/tobacco use
Azithromycin 500 mg PO day 1,
 Pregnancy (+), 1st trimester
250 mg PO days 2-5 (currently
on day 3)
 BP today= 128/78
MVI one PO daily
 HR=78
Citracal® Petite one PO BID
Which treatment is most appropriate for E.C.’s
hyperthyroidism?
a.
b.
c.
d.
Methimazole 15 mg PO daily
Methimazole 15 mg PO BID
Propylthiouracil 100 mg PO TID
Radioactive iodine
Side effects
Compliance
Pregnancy
Education
and
Identification
Symptom
Control
Importance of
monitoring &
follow-up
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Smoking and
smoking
cessation
[email protected]
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