Download management of h poth roidism - Canadian Healthcare Network

Free
C
Continuing Education Lesson
answering options
A. For immediate results, answer online
at www.pharmacygateway.ca.
B. Mail or fax the printed answer card
to (416) 764-3937. Your reply
card will be marked and you will be
advised of your results within six to
eight weeks in a letter from Rogers
Publishing.
APPROVED FOR
1.25 CE UNITS
Approved for 1.25 CE units by the Canadian Council
on Continuing Education in Pharmacy. File #492-1106.
Not valid for CE credits after DECEMBER 14, 2009.
Management
of h poth roidism
By Mário L de Lemos Feb 2007
The author, expert reviewers and Pharmacy Practice magazine have each declared that there is
no real or potential conflict of interest with the sponsor of this CE lesson.
OBJECTIVES
Upon successful completion of this
lesson, the pharmacist will be able to:
1.discuss the clinical presentation of
hypothyroidism
2.discuss the role of thyroid function tests in
the management of hypothyroidism
3.review the use of thyroid hormones in the
management of hypothyroidism
4.review the controversy of using combined
thyroid hormone therapy
5.recommend appropriate management of
hypothyroidism
Instructions
1.After carefully reading this lesson, study
each question and select the one answer
you believe to be correct. Circle the
appropriate letter on the attached reply
card.
2.To pass this lesson, a grade of 70% (14 out
of 20) is required. If you pass, your CEU(s)
will be recorded with the relevant provincial
authority(ies). (Note: some provinces require
individual pharmacists to notify them.)
This CE lesson is published by Rogers Publishing
Limited (Pharmacy Group), One Mount Pleasant
Rd., Toronto, Ont. M4Y 2Y5. Tel.: (416) 764-3916
Fax: (416) 764-3931. No part of this CE lesson
may be reproduced, in whole or in part, without
the written permission of the publisher. ©2007
Hypothyroidism is the most common thyroid disorder (1.4-2% in women, 0.12.0% in men).1 It occurs when the thyroid
gland produces insufficient thyroid hormone. The incidence increases with old
age, such that it rises to 6% in women and
2.5% in men older than 60 years of age.1
Most patients need long-term replacement
of their thyroid hormones. Therefore, it
would be useful for pharmacists in general
practice to familiarize themselves with the
management of hypothyroidism. This lesson provides an overview of its management, with a focus on the role of the pharmacist in optimally assisting the care of
adult patients.
carried throughout the body to help regulate growth and metabolism.2
The thyroid gland is controlled by a
feedback loop along the axis of the hypothalamus, anterior pituitary gland, and the
thyroid gland. When the circulating thyroid hormones become too low, the pituitary produces thyroid-stimulating hormone (TSH, thyrotropin). The TSH then
stimulates the thyroid gland to produce
more hormones. Conversely the pituitary
gland reduces TSH production when it detects a high level of circulating thyroid
hormones. The pituitary gland itself is
controlled by the hypothalamus via the
TSH-releasing hormone (TRH), which
tells the pituitary to stimulate the thyroid
gland.2
Thyroid gland
Thyroid hormones
The thyroid gland is located at the base of
the neck. It consists of two lobes joined by
a narrow band of tissue (the isthmus) that
is just below the cricoid cartilage near the
“Adam’s apple”. The thyroid gland takes
iodine from foods and incorporates it into
thyroid hormones. These hormones are
then released into the bloodstream and
The thyroid gland produces two major
hormones: thyroxine (levothyroxine, T4)
and triiodothyronine (liothyronine, T3). A
major component of these hormones is the
trace element iodine. Dietary iodine is
concentrated by the thyroid gland for the
synthesis of T3 and T4. T3 is about four
times more potent than T4. About 20% of
Introduction
SUPPORTED BY AN UNREstricted EDUCATIONAL GRANT FROM
circulating T3 is secreted by the thyroid
gland, while the remaining 80% is derived
from peripheral deiodination of T4 by 5’monodeiodinase.3 Due to protein binding,
T4 has a half-life of about seven days.3 In
contrast, the more potent T3 has a half-life
of only one to two days.3,4
Thyroid hormones act on multiple organ systems. One of the major physiologic
effects involves the maintenance of the
basal metabolic rate. Thyroid hormones
increase oxygen consumption and heat
production in all body tissues except the
brain, spleen and testis. Not surprisingly,
patients with hypothyroidism often experience increased sensitivity to cold temperature.2
Causes of hypothyroidism
Hypothyroidism is due to a problem in the
thyroid gland in nearly 95% of cases (primary hypothyroidism). Rarely, secondary
hypothyroidism may be caused by decreased production of TSH by the anterior
pituitary gland (see Thyroid Gland above
on the hypothalamus-pituitary-thyroid
axis). Hashimoto’s thyroiditis is the most
common cause of primary hypothyroidism. It is more prevalent in women and the
incidence generally increases with age.5
This is an autoimmune disorder in which
thyroid cells are destroyed by circulating
thyroid antibodies. As a result, patients develop inactive thyroid hormones or insufficient amounts of active thyroid hormones
to maintain normal thyroid state (euthyroid).1 Unfortunately, autoimmune thyroiditis is usually chronic and permanent.5
Iatrogenic causes
Of particular relevance to pharmacists,
certain medications have been associated
with hypothyroidism: high doses of iodine,
iodinated contrast agents, amiodarone
(can also cause hyperthyroidism), lithium,
interferon-alfa, and interleukin-2.1 Also,
sulfonamides, sulfonylureas and thalidomide have sometimes been implicated.2
Treatment of thyroid cancer can also
cause hypothyroidism as a result of the
surgical removal of thyroid gland (thyroidectomy) and destruction of thyroid tissue
by radioactive iodine treatment (131I therapy). Radiation therapy of the neck region
for some cancers may also cause hypothyroidism in a dose-dependent manner. In
this case, patients may have asymptomatic
hypothyroidism at the beginning before
| Management of hypothyroidism
progressing to clinical disease after a number of years.6
Iodine deficiency
As mentioned before, iodine is an essential
component of the thyroid hormone. Since
it must come from dietary sources, iodine
deficiency (less than 100 microgram/day)
is the most common cause of hypothyroidism worldwide. However, this is rare in
Canada because salt is usually iodized and
dietary sources of iodine are easily available. The recommended daily intake of
iodine is 150 microgram for adults. For
women, an increased intake of iodine is
needed during pregnancy (220 microgram/day) or when breastfeeding (290 microgram/day).7
Iodine deficiency leads to reduced production of thyroid hormones, triggering
the feedback loop of the hypothalamus-pituitary-thyroid axis (see Thyroid Gland
above for more details on the feedback
loop). As a result, the anterior pituitary
gland increases TSH secretion to restore
the thyroid hormones to normal level.
However, TSH also promotes the growth
of the thyroid gland, leading to the development of goiter. It should be noted that
hypothyroidism occurs when iodine intake
is very low. If iodine deficiency is not severe, hyperthyroidism may develop instead
because of the continued growth of one or
more TSH-dependent thyroid nodules.2
Goiter may also be associated with hyperthyroidism.8
Clinical presentation
Symptoms at presentation may be minimal or involve a variety of organ systems.
This is not surprising given the extensive
involvement of the thyroid hormones in
the body.2 Patients may experience a general “slowing down” of the body due to
reduced thyroid hormones to maintain the
function of body systems and metabolic
processes (see Table 1). Some of these nonspecific symptoms may resemble normal
changes in aging, thus making diagnosis
difficult in the elderly.9 Symptom development depends on the severity and onset of
hypothyroidism. Generally, milder symptoms are associated with hypothyroidism
that has developed over a longer period of
time. Rarely, patients may have life-threatening symptoms such as myxedema coma.
Myxedema coma
Rarely, myxedema coma may occur due to
prolonged, severe hypothyroidism, sometimes triggered by acute illness (e.g., infection). Patients may present with decreased
mental status and hypothermia. Other
symptoms include hypotension, bradycardia, hyponatremia, hypoglycemia, and hypoventilation. Myxedema coma is a medical emergency as it can be highly fatal.
Patients need to be treated aggressively
with thyroid hormone and supportive
measures, as well as treatment of any precipitating causes.2
Transient hypothyroidism
Patients with non-autoimmune (e.g., postpartum) or subacute thyroiditis may experience transient hyperthyroidism, followed
by transient hypothyroidism before recovery of thyroid function. The hypothyroidism is usually more severe in patients with
subacute thyroiditis, while sometimes patients with painless thyroiditis may present
during the hypothyroid phase of the illness. In women with postpartum thyroiditis, hypothyroidism may last from weeks
to months.2
Laboratory investigations
TSH and free T4 are commonly used in
the diagnosis and monitoring of hypothyroidism. Total T4 is usually not needed
when free T4 is available. Total or free T3
are less sensitive indicators of hypothyroidism.12
TSH
This is the most common initial test for
investigation. An elevated TSH (usual
range, 0.4-4.5 mIU/L) is the most sensitive indicator of hypothyroidism. If TSH
is within range, no further testing is usually indicated. Subclinical hypothyroidism
can be defined by an elevated TSH with
normal thyroid hormone levels.2 Some
drugs may decrease TSH secretion (prednisone ≥20 mg/day, octreotide, bexarotene, metformin).13
Serum free T412
If TSH is elevated, a diagnosis of hypothyroidism is usually confirmed with a low
free T4. Patients with an elevated TSH and
a low free T4 may also be tested for antithyroid antibody test (e.g., antithyroid
peroxidase) to determine if it is caused by
automimmune thyroiditis. Again as with
Answer online at www.pharmacygateway.ca | February 2007
TaBLE 1: Common hypothyroid symptoms and physical findings1,3,10,11
Most commonLess common
• intolerance to cold temperatures • trouble sleeping
• weight gain
• puffiness around the eyes
• constipation
• anxiety
• coarse features
• depression
• dry eyes, skin and hair
• changes in menstrual cycle
• slow heart beat
• joint pains
• hoarseness • headache
• slow mental processing • deafness (including in elderly)
• fatigue, muscle aches or weakness • loss of taste/smell
• delayed deep tendon reflexes
• decreased sweating
• shortness of breath
• slow speech
• anemia
• hyponatremia
• elevated cholesterol and
triglyceride levels
TSH, some drugs may alter total and/or
serum T4 level (see Drug Interactions).
Thyroid function in nonthyroid illness
Some patients with serious nonthyroid illnesses (e.g., starvation, infections, serious
chronic conditions) can present with low
total or free T4. However, their TSH level
may remain within normal range. This has
been described as euthyroid sick syndrome
but it may also be an acquired form of
transient hypothyroidism.14 Since they
may have normal TSH despite low T4 levels, routine thyroid function tests may be
unreliable.15 Also, it is unclear if they
should be treated with thyroid hormone
since the thyroid changes may be a natural
protection against excessive tissue catabolism.16
Drug therapy of
hypothyroidism
Thyroid hormone products
The goal of therapy is to normalize the
TSH level (euthyroid state). This is usually
achieved with T4 replacement therapy.
Synthetic forms of both T4 (Synthroid,
Eltroxin, Euthyrox) and T3 (Cytomel) are
available, although the supply of the latter
has been inconsistent. Desiccated thyroid
hormone containing T4 and T3 is also
available but the actual amounts of thyroid
hormones may be erratic.17-19
T4
Synthetic T4 (levothyroxine) is generally
the drug of choice for hypothyroidism. T4
February 2007 | Answer online at www.pharmacygateway.ca
can theoretically provide stable and physiological quantities of T3 due to its long
half-life (6-7 days) and peripheral conversion to T3 (see Controversy below). Optimal absorption is with an empty stomach.20
T3
The more potent T3 has a half-life of one
to two days and reaches peak levels two to
four hours after oral administration.3,4 Although T3 can be dosed once daily, serum
T3 levels may fluctuate widely because of
rapid gastrointestinal absorption and
shorter half-life in the circulation.21 T3 is
also best taken with an empty stomach.3,4
Dosing considerations
The usual T4 dose range is 0.5–1.8 microgram/kg3 and the average replacement
dose is about 1.6-1.7 microgram/kg once
daily (i.e., about 100-125 microgram once
a day).1 Patients are generally started at the
lower end of the anticipated dose requirement (e.g., 50 microgram/day) and titrated upwards by 25–50 microgram increments. T3 is usually started at 25
microgram/day and increased by up to 25
microgram every one to two weeks until
the usual maintenance dose of 25–75 microgram/day is reached.4 See also special
dosing adjustments for patients with cardiovascular problems and elderly in the
Monitoring section.
Monitoring12
Overdosing and underdosing of thyroxine
is not uncommon.21,22 TSH is the most
common laboratory parameter used to
help monitor the therapy. However, TSH
values only change slowly as it is a surrogate of the thyroid hormones at the serum
or tissue level. Hence, TSH level is usually
measured about four to eight weeks after
starting T4 therapy or a change in dose.12,23
Once the T4 dose is stabilized, TSH may
be measured annually or more often as
clinically indicated.12 This includes certain
life changes such as pregnancy, menopause,
etc. If TSH is within normal range, no
dose adjustment is usually indicated. If
TSH is below reference range, it may be
appropriate to ensure that the patient is
not hyperthyroid by obtaining additional
free T4 levels.24
Dosage adjustment may be considered if
TSH is excessively suppressed. Patients
with no symptoms of hyperthyroidism and
a slightly reduced TSH may be continued
at the same dose. Excess T4 replacement
can increase the risk of bone loss and irregular heart beat, especially in elderly patients.3 However, borderline hyperthyroidism may be beneficial in patients whose
hypothyroidism resulted from removal or
ablation of thyroid cancer. This is because
TSH suppression may potentially inhibit
stimulation of any residual thyroid cancer
cells. For these patients, some suggest to
reduce TSH to an undetectable level for
the first five years after surgery and stabilize at the lower end of the normal range
thereafter.25
Serum thyroglobulin (Tg) level and
radioiodine scanning may be part of the
follow-up monitoring for patients after
ablation of thyroid cancer. An increase in
Tg or iodine uptake would indicate
residual thyroid tissue or thyroid cancer.
Optimal results of Tg testing and
radioiodine scanning require elevated TSH
levels. This is usually achieved by
temporarily withdrawing thyroid hormone
replacement. Since this may lead to
symptoms of hypothyroidism, an
alternative is to use the recombinant form
of TSH, thyrotropin alfa (Thyrogen®), to
stimulate iodine uptake and secretion of Tg.2
Overtreatment with thyroid hormones
can lead to symptomatic thyrotoxicosis
(e.g., increased metabolic rate and heart
rate, hypertension), increased risk of osteoporosis, as well as a worsening of pre-existManagement of hypothyroidis | ing cardiac symptoms.3 Since thyroid hormones act on the heart by increasing the
force (inotropic) and the rate (chronotropic) of cardiac contraction, patients with
ischemic heart disease should be started on
a lower T4 dose (e.g., 25 microgram/day)
and titrated in increments of 12.5–25 microgram every four to six weeks.3 Older
patients may also need to be started at a
lower dose (e.g., 25-50 microgram/day)
and have their dose reassessed annually.26,27
In contrast, patients with previous thyroid
ablation (because of cancer) may need
higher doses because there is little residual
functioning thyroid tissue.
T4 is safe in pregnant women as it does
not cross the placenta in significant
amounts. However, the dose of T4 may
need to be increased (e.g., by 50%) to
maintain euthyroid state in these patients
since TSH level is elevated during pregnancy.28 Also, it is important to ensure euthyroid state in these women even if they
exhibit few symptoms, since subclinical
hypothyroidism may nevertheless affect
the development of the fetus (e.g., placental abruption, preterm delivery, low birth
weight, impaired neuropsychological cognition).29
Controversy of
interchangeability
Two similarly formulated products may be
described as bioequivalent if they have the
same amount of the drug and comparable
pharmacokinetic properties (e.g., dissolution, area under the curve, maximum plasma drug concentration). For most drugs,
the established assumption is that bioequivalence implies therapeutic equivalence.35,36 To date, however, bioequivalence
has not been established between the levothyroxine products in Canada. Nevertheless, some products may be deemed interchangeable for reimbursement purposes,
depending on the province.37 If a switch
has been made, pharmacists should be
aware of potential differences between
products and notify patient and prescriber
for any dose adjustment or laboratory testing.
In the U.S., bioequivalence has been established for some levothyroxine products.
However, it has been suggested that more
stringent criteria are needed to establish
bioequivalence for levothyroxine which
may have a narrow therapeutic range
(NTR).38 Health Canada does not consid | Management of hypothyroidism
Table 2: Drug interactions with thyroid hormone or thyroid function tests
estrogen1,13,30
• increases TBG, raises total T4, lowers free T4, increases TSH; may need higher T4 dose
tamoxifen, raloxifene,
• increase TBG, raise total T4; no effect methadone, fluorouracil1,13 on free T4 or TSH
androgens, anabolic steroids,
• lower TBG, lower total T4; no effect on glucocorticoids1,13 free T4 or TSH
anti-inflammatory doses of
• block T4 binding to TBG, lower total salicylates ≥2g/day1,13 T4; no effect on free T4 or TSH
calcium carbonate, aluminum • lower oral absorption; separate
hydroxide gel, sucralfate, administration times (calcium cholestyramine, iron3,31 carbonate, aluminum hydroxide: by 4 hours; sucralfate: by 8 hours; cholestyramine: by 6 hours; iron: by as much as possible)
drugs that suppress gastric • decrease oral absorption; may need acid secretion32 higher T4 dose
phenobarbital, rifampin, phenytoin, • increase T4 metabolism; may need carbamazepine13 higher T4 dose
imatinib33
• increases T4 metabolism; may need higher T4 dose
amiodarone1,3,31
•complex interaction with thyroid function tests, lowers peripheral and pituitary conversion of T4 to T3; may need higher T4 dose for pre-existing hypothyroidism
dopaminergic agonists (e.g., • antagonizes stimulatory effects of levodopa, bromocriptine), TRH and hence suppresses TSH secretion glucocorticoids1,3,31
metoclopramide, domperidone1,3,31 • increases TSH secretion by blocking dopaminergic receptors
digoxin
• digoxin level may be reduced34
theophylline
• decreased theophylline clearance in hypothyroid patients34
warfarin
• thyroid hormones increase anticoagulation34
TBG = thyroid binding globulin
T4 = levothyroxine
T3 = liothyronine TRH = TSH-releasing hormone
TSH = thyroid stimulating hormone, thyrotropin
er levothyroxine to have a NTR39 although
it may potentially be a critical dose drug.39
Small changes in dose of such a drug may
lead to serious therapeutic failures and/or
adverse drug reactions.40 Bioequivalence
testing for critical dose drug allows narrower variability limits (90-112%) in plasma drug concentration between products
than other drugs (80-120%). Currently,
levothyroxine has not been included in
Health Canada’s bioequivalence guide for
critical dose drug.40
Finally, it has been suggested that therapeutic equivalence can only be based on
clinically equivalent TSH.38 This calls into
the question the established assumption
that bioequivalence implies therapeutic
equivalence.35 Note that since TSH is a
secondary response to levothyroxine administration, TSH level may fluctuate in
Answer online at www.pharmacygateway.ca | February 2007
the same patient or between patients even
if the same product is used. Also, the degree of fluctuation may potentially be
greater than that of the plasma T4 level,
which results more directly from the levothyroxine administration.
Controversy of combined
thyroid hormone (T4/T3)
therapy
The use of T4 monotherapy as the standard treatment is based on the assumption
that peripheral conversion of T4 to T3 can
provide the appropriate amount of T3
needed at the tissue action site. However,
it has been suggested that clinically this
may not be the case in some patients, who
may continue to experience hypothyroid
symptoms despite “adequate” T4 dosing.41
In animals, it has been shown that a combination of both types of thyroid hormones
is needed to provide sufficient T4 and T3
at the tissue level.42 There are, of course,
inherent interspecies differences in thyroid
hormone metabolism (e.g., T4/T3 ratio,
serum transport, tissue metabolism), so it
is not clear if this is happening similarly in
humans.43
Clinical trials comparing T4 monotherapy with T4/T3 combination therapy
Several randomized clinical trials have directly compared the efficacy of T4 monotherapy against a combination of T4 and
T3. Overall, there is limited evidence to
suggest that combination replacement
therapy would provide better symptom
control than T4 alone.44-53 Bunevicius et
al. provided the main evidence on the potential benefits of combination therapy.45
In their investigation, they compared T4
(average 175 microgram/day) with a combination of T4 and T3 in 33 hypothyroid
patients. The combination regimen consisted of substituting 50 microgram of the
usual T4 daily dose with 12.5 microgram
of T3). Patients treated with the combination therapy reported better improvement
in their quality of life (QOL), mood and
psychometric performance than those on
T4 therapy alone. In a subgroup analysis
of 26 female patients, combination T4/T3
therapy was also found to be superior in
mental improvement in 15 patients whose
hypothyroidism was due to thyroid ablation, possibly because they were more dependent on exogenous hormone.46
Other investigators have followed simiFebruary 2007 | Answer online at www.pharmacygateway.ca
lar comparisons of T4 vs. T4/T3 therapy
in several studies involving a total of 936
patients. The combination of T4 and T3
therapy followed one of two strategies: either partially substituting T4 dose with a
fixed dose of T347-50 or a using a regimen
with fixed T4:T3 molar ratio.51-53 Overall,
findings from these follow-up studies failed
to confirm that a combination of T4 and
T3 was significantly better than T4 alone
in terms of QOL,47,49,51-53 mood50,53 and
cognitive function.47-49,51-53 However, there
were some patients who seemed to prefer
the combination therapy to T4 alone even
though they did not show any marked improvement in QOL,47,52,53 mood53 or cognitive function.47,52,53 Hence, it is possible
that the clinical parameters used in these
studies may not have captured the difference in all the therapeutic effects between
the two types of regimens.41
THE PHARMACIST’S ROLE
Pharmacists can assist patients with hypothyroidism in several ways. First, patients
must be informed that thyroid hormone
replacement is, in many cases, a life-long
therapy. Hence, patients should have a
good understanding of the purpose of the
therapy in order to have long-term compliance. This is particularly important given the relatively narrow therapeutic index
of the thyroid hormones. Patients should
be careful not to hoard the remaining supply of different strengths of T4 which may
have been given from previous prescriptions, as this may potentially lead to making up the wrong doses.
Secondly, the bioavailability of T4 is affected by food and various drug interactions. The pharmacist can tailor the daily
dosing time for the patients based on any
concurrent medications that may interact
with T4. In addition, there are drug interactions that may warrant attention of the
patient and physician to adjust the dosing
of T4 and/or interacting agents, as well as
affect the interpretation of the thyroid
function tests.
Finally, pharmacists should be aware of
potential differences between products. If
a switch of product has been made, the patient and prescriber may need to be notified so any dose adjustment or laboratory
tests can be made.
CONCLUSION
Hypothyroidism is a common thyroid
disorder that usually requires long-term
therapy. Optimal management usually
involves the use of thyroid hormones,
which require accurate dosing and
awareness of various drug interactions.
Regular monitoring with TSH and other
thyroid function tests is essential to
maintain these patients in euthyroid state.
References
1. Dong BJ. Thyroid disorders. In: Koda-Kimble M, Young L,
Wayne A, Guglielmo B, editors. Applied therapeutics: The clinical
use of drugs. Baltimore, MD: Lippincott Williams & Wilkins;
2001.
2. Greenspan FS. The Thyroid Gland. In: Greenspan FS, Gardners DG, editors. Basic and Clinical Endocrinology. 7th ed. Montreal, Quebec: McGraw-Hill Medical; 2004. p. 215-94.
3. Roberts CG, Ladenson PW. Hypothyroidism.[see comment]. Lancet 2004;363(9411):793-803.
4. Cytomel. In: Repchinsky C, editor. Compendium of Pharmaceutical and Specialties. 40th ed. Ottawa, Ontario: Canadian
Pharmacists Association; 2005.
5. Hayashi Y, Tamai H, Fukata S, et al. A long term clinical,
immunological, and histological follow-up study of patients with
goitrous chronic lymphocytic thyroiditis. J Clin Endocrinol Metab
1985;61(6):1172-8.
6. Hancock SL, Cox RS, McDougall IR. Thyroid diseases after
treatment of Hodgkin’s disease. N Engl J Med 1991;325(9):599605.
7. Anonymous. Iodine: Drug information. In: Rose B, editor.
UpToDate. Wellesley, MA: UpToDate 14.2; 2006.
8. Rieu M, Bekka S, Sambor B, et al. Prevalence of subclinical
hyperthyroidism and relationship between thyroid hormonal status and thyroid ultrasonographic parameters in patients with
non-toxic nodular goitre. Clin Endocrinol (Oxf) 1993;39(1):6771.
9. Laurberg P, Andersen S, Bulow Pedersen I, et al. Hypothyroidism in the elderly: Pathophysiology, diagnosis and treatment.
Drugs Aging 2005;22(1):23-38.
10. Hanna FW, Scanlon MF. Hyponatraemia, hypothyroidism,
and role of arginine-vasopressin. Lancet 1997;350(9080):7556.
11. O’Brien T, Dinneen SF, O’Brien PC, et al. Hyperlipidemia in
patients with primary and secondary hypothyroidism. Mayo Clin
Proc 1993;68(9):860-6.
12. Guidelines and Protocols Advisory Committee. Thyroid
function tests in the diagnosis and monitoring of adults with
thyroid disease. Victoria, BC: BC Health Services; 1 October
2004.
13. Surks MI. Drug interactions with thyroid hormones. In:
Rose B, editor. UpToDate. Wellesley, MA: UpToDate 14.2; 8 May
2006.
14. Chopra IJ. Clinical review 86: Euthyroid sick syndrome: Is
it a misnomer? J Clin Endocrinol Metab 1997;82(2):329-34.
15. Stockigt JR. Guidelines for diagnosis and monitoring of
thyroid disease: Nonthyroidal illness. Clin Chem 1996;42(1):18892.
16. Utiger RD. Altered thyroid function in nonthyroidal illness
and surgery. To treat or not to treat? N Engl J Med
1995;333(23):1562-3.
17. Rees-Jones RW, Rolla AR, Larsen PR. Hormonal content of
thyroid replacement preparations. JAMA 1980;243(6):549-50.
18. Csako GA, Cetnarowski-Cropp AB, Pucino F. Therapeutic
potential of two over-the-counter thyroid hormone preparations.
Management of hypothyroidis | Dicp 1990;24(1):26-7.
19. Sawin CT, London MH. ‘Natural’ desiccated thyroid. A
‘health-food’ thyroid preparation. Arch Intern Med
1989;149(9):2117-8.
20. Benvenga S, Bartolone L, Squadrito S, et al. Delayed intestinal absorption of levothyroxine. Thyroid 1995;5(4):249-53.
21. Parle JV, Franklyn JA, Cross KW, et al. Prevalence and
follow-up of abnormal thyrotrophin (TSH) concentrations in the
elderly in the United Kingdom. Clin Endocrinol (Oxf)
1991;34(1):77-83.
22. Hollowell JG, Staehling NW, Flanders WD, et al. Serum
TSH, T(4), and thyroid antibodies in the United States population
(1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87(2):489-99.
23. Kaplan MM. Clinical perspectives in the diagnosis of thyroid disease. Clin Chem 1999;45(8 Pt 2):1377-83.
24. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines
for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 2002;8(6):457-69.
25. Ringel M, Ladenson P. Controversies in the follow-up and
management of well-differentiated thyroid cancer. Endocr Relat
Cancer 2004;11(1):97-116.
26. Sawin CT, Herman T, Molitch ME, et al. Aging and the
thyroid. Decreased requirement for thyroid hormone in older hypothyroid patients. Am J Med 1983;75(2):206-9.
27. Davis FB, LaMantia RS, Spaulding SW, et al. Estimation of
a physiologic replacement dose of levothyroxine in elderly patients with hypothyroidism. Arch Intern Med 1984;144(9):17524.
28. Mandel SJ, Larsen PR, Seely EW, et al. Increased need for
thyroxine during pregnancy in women with primary hypothyroidism. ������������������������������
N Engl J Med 1990;323(2):91-6.
29. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341(8):54955.
30. Arafah BM. Increased need for thyroxine in women with
hypothyroidism during estrogen therapy. N Engl J Med
2001;344(23):1743-9.
31. Levothyroxine. In: Drug interaction facts [book on CDROM]. St Louis, Missouri: Facts and Comparisons; January
2006.
32. Centanni M, Gargano L, Canettieri G, et al. Thyroxine in
goiter, Helicobacter pylori infection, and chronic gastritis. The N
Engl J Med 2006;354(17):1787-95.
33. de Groot JW, Zonnenberg BA, Plukker JT, et al. Imatinib
induces hypothyroidism in patients receiving levothyroxine. Clin
Pharmacol Ther 2005;78(4):433-8.
34. Facts and Comparisons 4.0. Levothyroxine. Conshohocken, Pensylvannia: Wolters Kluwer Health; 2006.
35. Health Canada. Guidance for industry. Conduct and analysis of bioavailability and bioequivalence studies -part A: oral
dosage formulations used for systemic effects. Ottawa, Ontario:
Minister of Public Works and Government Services Canada;
1992.
36. College of Pharmacists of British Columbia. Information
for Pharmacists: Drug Interchangeability Update. Vancouver, British Columbia: College of Pharmacists of British Columbia;
August 2004.
37. Ministry of Health. Ontario Benefit Drug Formulary/Comparative Drug Index No. 39. Toronto, Ontario: Publications Ontario; 27 September 2005. p. III.269.
38. American Association of Clinical Endocrinologists. AACE,
TES, ATA Joint Position Statement on the Use and Interchangeability of Thyroxine Products. Undated. Available from http://www.
aace.com/pub/positionstatements/. Accessed August 31,
2006.
| Management of hypothyroidism
39. Health Canada. Expert Advisory Committee on Bioavailability. Record of Proceedings. April 16, 2003. Available from
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/scicom/bio/sacbb_rop_ccsbb_crd_2003-04-16_e.html.
Accessed January 12, 2006.
40. Health Canada. Guidance for industry. Bioequivalence
requirements: Critical dose drug. Ottawa, Ontario: Minister of
Public Works and Government Services Canada; 31 May 2006.
41. Walsh JP. Dissatisfaction with thyroxine therapy - could
the patients be right? Curr Opin Pharmacol 2002;2(6):717-22.
42. Escobar-Morreale HF, del Rey FE, Obregon MJ, et al. Only
the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.
Endocrinology 1996;137(6):2490-502.
43. Escobar-Morreale HF, Botella-Carretero JI, del Rey FE, et
al. Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab
2005;90(8):4946-54.
44. Smith RN, Taylor SA, Massey JC. Controlled clinical trial of
combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Br Med J 1970;4(728):145-8.
45. Bunevicius R, Kazanavicius G, Zalinkevicius R, et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism.[see comment]. N Engl J
Med 1999;340(6):424-9.
46. Bunevicius R, Prange AJ. Mental improvement after replacement therapy with thyroxine plus triiodothyronine: relationship
to cause of hypothyroidism. Int J Neuropsychopharmacol
2000;3(2):167-74.
47. Walsh JP, Shiels L, Lim EM, et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life,
or cognitive function compared to thyroxine alone: A randomized
controlled trial in patients with primary hypothyroidism.[see
comment]. J Clin Endocrinol Metab 2003;88(10):4543-50.
48. Saravanan P, Simmons DJ, Greenwood R, et al. Partial
substitution of thyroxine (T4) with tri-iodothyronine in patients on
T4 replacement therapy: results of a large community-based
randomized controlled trial. J������������������������
Clin Endocrinol Metab
2005;90(2):805-12.
49. Clyde PW, Harari AE, Getka EJ, et al. Combined levothyroxine plus liothyronine compared with levothyroxine alone in
primary hypothyroidism: a randomized controlled trial.[see comment]. JAMA 2003;290(22):2952-8.
50. Sawka AM, Gerstein HC, Marriott MJ, et al. Does a combination regimen of thyroxine (T4) and 3,5,3‘-triiodothyronine improve depressive symptoms better than T4 alone in patients with
hypothyroidism? Results of a double-blind, randomized, controlled trial.[see comment]. J Clin Endocrinol Metab
2003;88(10):4551-5.
51. Siegmund W, Spieker K, Weike AI, et al. Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar
ratio 14 : 1) is not superior to thyroxine alone to improve wellbeing and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf) 2004;60(6):750-7.
52. Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno
M, et al. Thyroid hormone replacement therapy in primary hypothyroidism: A randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone.[summary for patients in Ann Intern
Med. 2005 Mar 15;142(6):I55; PMID: 15767615]. Ann Intern
Med 2005;142(6):412-24.
53. Appelhof BC, Fliers E, Wekking EM, et al. Combined therapy with levothyroxine and liothyronine in two ratios, compared
with levothyroxine monotherapy in primary hypothyroidism: A
double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab 2005;90(5):2666-74.
Answer online at www.pharmacygateway.ca | February 2007
QUESTIONS
1.What is the most common cause of
hypothyroidism in Canada?
a)pregnancy
b)autoimmune thyroiditis
c)decreased production of TSH by the anterior pituitary gland
d)iodine deficiency
e)acute infection
2.Which medication is the most likely to
have contributed to the symptoms of a
patient with hypothyroidism?
a)digoxin
b)theophylline
c)amiodarone
d)ramipril
e)simvastatin
3.Which medication can affect thyroid
function tests?
a��������������
)�����������
alendronate
b������������
)���������
glyburide
c������������
)���������
estrogens
d�����������
)��������
warfarin
e�������������
)����������
amlodipine
4.Which statement is TRUE concerning
the natural history of hypothyroidism?
a)It is the most common thyroid disorder in
Canada.
b)It is a precursor of thyroid cancer.
c)The incidence of hypothyroidism tends to
decrease with age.
d)Most cases of hypothyroidism are shortlived.
e)In general, hypothyroidism is more common in men than in women.
5.Which statement is TRUE on the dosing
of thyroid hormones?
a)The average adult dose of levothyroxine
is about 100-125 microgram once a day.
b)Most patients should be started at the
average dose of 100-125 microgram/day
and adjust dose according to clinical response.
c)The usual maintenance dose of levothyroxine (T4) and liothyronine (T3) are
similar.
d)Dosing of levothyroxine is usually independent of age or body weight.
e)In general, levothyroxine dose is similar
whether the patient is pregnant or not.
February 2007 | Answer online at www.pharmacygateway.ca
6.Which statement is FALSE regarding
the controversy of bioequivalence of
levothyroxine?
a)TSH is the primary response parameter
after administration of a dose of levothyroxine.
b)Different levothyroxine products contain
identical active ingredient.
c)Different levothyroxine products may be
considered interchangeable in different
provinces.
d)Health Canada has not included levothyroxine in its current list of critical dose
drugs.
e)Health Canada has recently announced
the bioequivalence testing criteria for
critical dose drug.
7.Which statement is TRUE regarding
combination therapy with T4 and T3?
a)Combination therapy has been shown to
be superior to T4 alone in all the randomized controlled trials.
b)Combination therapy has been shown to
be superior to T4 alone in some patients
in clinical trials.
c)Combination therapy usually consists of
using desiccated thyroid hormone product which contains both T4 and T3.
d)Combination therapy has been shown to
be consistently better than T4 alone in
improving the patient’s quality of life.
e)Combination therapy is the standard
management of choice for patients with
hypothyroidism.
8.Which statement is TRUE in patients
presenting with myxedema coma?
a)Patients may present with hypertension,
tachycardia and hyperventilation.
b)Patients may present with decreased
mental status and hypothermia.
c)Myxedema coma is usually self-limited
and reversible.
d)Most patients with myxedema coma respond well to discontinuation of thyroid
hormone therapy.
e)Myxdema coma is a common manifestation of hypothyroidism.
9.Which statement is FALSE regarding
drug interactions of thyroid hormones?
a)Calcium carbonate may reduce oral absorption of levothyroxine.
b)Digoxin may increase the oral absorption
of levothyroxine.
c)Levothyroxine may increase anticoagulation of warfarin.
d)Cholestyramine may reduce oral absorption of levothyroxine.
e)Patients on estrogen replacement therapy
may need higher doses of levothyroxine.
10.Which statement is TRUE regarding
drug interaction of thyroid hormones?
a)Patients on amiodarone may need higher
doses of levothyroxine.
b)Patients on phenytoin may need lower
doses of levothyroxine.
c)Patients on imatinib may need lower
doses of levothyroxine.
d)Patients on estrogen replacement therapy
may need lower doses of levothyroxine.
e)Patients on warfarin may need higher
doses of levothyroxine.
11.Which statement is TRUE regarding
administration of levothyroxine?
a)Levothyroxine should be taken after a
meal to increase oral absorption.
b)Levothyroxine should be taken with sulcrafate to minimize stomach upset.
c)Levothyroxine should be taken at different administration times than iron supplements.
d)Levothyroxine should be taken in the
morning to optimize daily hormonal
need.
e)Levothyroxine is usually administered at
night to optimize daily hormonal need.
12.What is a likely side effect of levothyroxine?
a)Bradycardia
b)Decreased mental function
c)Worsening of angina
d)Weight gain
e)Increased tiredness
13.What is a common clinical symptom
associated with hypothyroidism?
a)intolerance to cold temperatures
b)worsening of angina
c�����������
)��������
insomnia
d���������������
)������������
hypertension
e�����������������
)��������������
hallucinations
Management of hypothyroidis | QUESTIONS continued
14.What is a possible long-term adverse
effect of levothyroxine overdosing?
a)hair loss
b)bone loss
c�������������
)����������
depression
d���������
)������
anemia
e���������������
)������������
constipation
15.Which statement is FALSE regarding
monitoring of levothyroxine therapy?
a)Underdosing of levothyroxine therapy is
not uncommon.
b)TSH is the most commonly used laboratory parameter for monitoring.
c)TSH is usually repeated twice a week
within the first week of initiating levothyroxine.
d)Total T4 level is usually not needed.
e)Free T3 level is usually not needed.
16.Which statement is FALSE regarding
the laboratory tests commonly used for
hypothyroidism?
a)TSH is usually the initial test for the diagnosis of hypothyroidism.
b)TSH is usually the routine test for the
monitoring of levothyroxine therapy.
c)Total T4 is usually the initial test for the
diagnosis of hypothyroidism.
d)Free T4 is usually used in conjunction
with TSH for the diagnosis of hypothyroidism.
e)Total and free T3 are not usually measured at the initial diagnosis of hypothyroidism.
17.Which statement is TRUE regarding the
clinical presentation of hypothyroidism?
a)All patients with clinical hypothyroidism
present with intolerance to cold temperatures.
b)Patients with underlying ischemic heart
disease usually experience worsening of
angina when developing hypothyroidism.
e)Advising patients that T4 can be taken
orally with or without food.
c)Patients with hypothyroidism may present with minimal symptoms even though
thyroid function tests may be abnormal.
d)Patients with serious nonthyroid illness
do not usually exhibit abnormal thyroid
function test results.
e)Patients with hypothyroidism due to autoimmune thyroiditis usually recover
without further treatment.
20.Which statement is FALSE regarding women with hypothyroidism during
pregnancy?
a)They usually need a higher dose of thyroid hormones during pregnancy.
b)They should take T3 instead of T4 as the
latter can cross the placenta in significant amounts.
c)They may have an elevated TSH level.
d)They should be maintained at euthyroid
even if they do not show overt clinical
symptoms.
e)They can expect to reduce T4 dose postpartum to pre-pregnancy level.
18.Which statement is FALSE regarding
the T4 and T3?
a)T4 is usually the drug of choice for hypothyroidism.
b)T4 has a longer half-life than T3.
c)T3 administered orally is usually converted into T4 at the tissue level.
d)A combination of T4 and T3 replacement
has been used for the management of hypothyroidism.
e)T3 has a quicker onset than T4 after oral
administration.
19.Some of the roles that the pharmacist can play to help patients optimize
thyroid hormone therapy include:
a)Advising patients that the therapy is
usually short-term and hence should not
have to worry about missing doses.
b)Advising patients on the potential for
any drug interactions that may occur.
c)Advising patients that the precise dose
of thyroid hormones is not particularly
important as they give similar effects at
different doses.
d)Advising patients that TSH is usually
taken within one week of any change in
T4 dose because its onset of action is
usually quick.
FACULTY:
About the author
Mario de Lemos is the Provincial Drug
Information Coordinator at the BC Cancer
Agency in Vancouver. He is an expert
reviewer for the forthcoming 5th edition
of the Therapeutic Choices by the Canadian
Pharmacists Association.
| Management of hypothyroidism
Reviewers
All lessons are reviewed by pharmacists for
accuracy, currency and relevance to current
pharmacy practice.
CE Coordinator
Heather Howie, Toronto, Ont.
For information about CE marking, please
contact Mayra Ramos at (416) 764-3879,
fax (416) 764-3937 or mayra.ramos@rci.
rogers.com. No part of this CE lesson may
be reproduced, in whole or in part, without
the written permission of the publisher.
©2007
Answer online at www.pharmacygateway.ca | February 2007
TO ANSWER THIS CE LESSON ONLINE
If currently logged into our ONLINE CE PROGRAM, please return to the "Lessons Available Online"
Page and click on "Link to questions" for this CE Lesson.
If not logged in but already registered to our ONLINE CE PROGRAM, please click here:
http://ce.pharmacygateway.com/Pharmacy/login/index.asp
If you have not registered for our ONLINE CE PROGRAM and wish to answer online, please click
here:
http://ce.pharmacygateway.com/Pharmacy/login/adduser.asp
If you have any questions. Please contact:
Pharmacy Practice, Pharmacy Post, Novopharm CE Compliance Centre, More CCCEP-approved CE’s, or Tech
Talk (English and French CE's)
Mayra Ramos
Fax: (416) 764-3937 or
email: [email protected]
Quebec Pharmacie and L'actualite Pharmaceutique
Stephane Paradis
Fax: (514) 843-2183
email: [email protected]