CME
Subclinical hypothyroidism:
To treat or not to treat?
Chelsea Simon, MPAS, PA-C; Emily Weidman-Evans,
PharmD, BC-ADM; Sarah Allen, MPAS, PA-C
Downloaded from https://journals.lww.com/jaapa by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3tjcLwhL8g9bZhhig7WeJvlKO387eh376aUD+EhEx1NRdgvwjaJZk6Q== on 08/21/2020
ABSTRACT
Subclinical hypothyroidism affects 4.3% of the US popula-
tion. Despite this prevalence, whether to treat or to observe
patients with subclinical hypothyroidism remains contro-
versial. Guidelines for overt hypothyroidism strongly favor
treatment for symptomatic benefits, but the same benefits of
levothyroxine treatment have not been proven for patients
with subclinical hypothyroidism—most likely due to the
asymptomatic nature of the condition. Additionally, a connec-
tion between subclinical hypothyroidism and cardiovascular
complications has not been definitively established, although
the evidence favors a relationship. This article describes the
background, presentation, and diagnostics of subclinical
hypothyroidism, treatment, and potential cardiovascular
complications, so clinicians can decide if initiating treatment
is best for their patients with subclinical hypothyroidism.
Keywords: subclinical hypothyroidism, cardiovascular
risk, levothyroxine, guidelines, goiter, overt
Learning objectives
List the patient populations most likely to benefit from the
diagnosis and treatment of subclinical hypothyroidism.
Outline a plan for the laboratory diagnosis of subclinical
hypothyroidism.
Describe the relationship between thyroid disease and car-
diovascular risk factors.
A
68-year-old woman presents to your clinic to
establish care after 20 years without a clinician.
Her only complaint is mild fatigue that has been
occurring for a year or more. A thorough history reveals
no significant past medical conditions and a family history
that is remarkable for coronary heart disease (father) and
stomach cancer (brother). A comprehensive physical exam-
ination is unremarkable. Basic screening laboratory tests
are ordered, including a thyroid-stimulating hormone
JAAPA Journal of the American Academy of PAs
Copyright © 2020 American Academy of Physician Assistants
CK
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(TSH) level, which returns elevated at 9.2 mU/L. The
patient returns to the clinic for a free thyroxine (T4) value,
which is found to be within normal limits. She is diagnosed
with subclinical hypothyroidism. Should she be started on
levothyroxine therapy?
This question is one that many clinicians have asked
since thyroxine became the standard of treatment for
hypothyroidism in 1950.1 Unlike overt hypothyroidism,
which is treated with levothyroxine for symptomatic relief
and cardiovascular disease (CVD) risk reduction, the treat-
ment recommendations for subclinical hypothyroidism
remain controversial; studies are conflicting on whether
patients with subclinical hypothyroidism receive similar
benefits with levothyroxine therapy. This article discusses
subclinical hypothyroidism, treatment recommendations,
and whether levothyroxine therapy is beneficial for patients,
especially concerning CVD risk reduction.
CAUSES AND EPIDEMIOLOGY
The most common form of hypothyroidism is primary
hypothyroidism, caused by a defect in the thyroid gland’s
synthesis and release of thyroid hormone.2 Iodine deficiency
is the most common cause of primary hypothyroidism
worldwide. The most common cause of primary hypothy-
roidism in iodine-sufficient areas is autoimmune (Hashi-
moto) thyroiditis, which is associated with antithyroid
peroxidase (anti-TPO) antibodies. Other possible causes
At the time this article was written, Chelsea Simon was a student in
the PA program at LSUHSC School of Allied Health in Shreveport, La.
She now practices at University Medical Center Interventional Radiol-
ogy in New Orleans, La. Emily Weidman-Evans is a clinical professor
and director of assessment, and Sarah Allen is an instructor in the
PA program at LSUHSC School of Allied Health. The authors have
disclosed no potential conflicts of interest, financial or otherwise.
DOI:10.1097/01.JAA.0000660120.03250.55
Copyright © 2020 American Academy of PAs
www.JAAPA.com 21
CME
Key points
Subclinical hypothyroidism is more common than overt
hypothyroidism, but evidence about its treatment is not
clear-cut.
The standard of practice is to treat any patient with a
TSH greater than 10 mU/L, as well as patients with
a lower TSH who are under age 70 years, pregnant,
women who are infertile, have a symptomatic goiter, have
antithyroid peroxidase antibodies, or have a high risk of
cardiovascular disease.
Studies support a relationship between subclinical
hypothyroidism and an increase in cardiovascular risk;
however, research about the benefits of levothyroxine for
reducing this risk is not conclusive, requiring a comparison
of potential advantages to the risk of treatment.
include external radiation exposure, thyroidectomy, and
infiltrative processes such as lymphoma, sarcoidosis, and
hemochromatosis.
Primary hypothyroidism can further be divided into overt
hypothyroidism and subclinical hypothyroidism.3 Sub-
clinical hypothyroidism is much more common than overt
hypothyroidism, affecting at least 4.3% of the US popula-
tion, compared with 0.3% who are affected by overt
hypothyroidism.2 The incidence of subclinical hypothyroid-
ism is greater in women, increases with age, and is more
common in white patients than black patients.4 Although
hypothyroidism is more commonly associated with iodine
deficiency, geographic areas or countries that are iodine-
sufficient have been shown to have higher incidences of
subclinical hypothyroidism than those that are insufficient
(about 6% incidence versus about 3%).4 Excess iodine
present in these areas is believed to inhibit iodine organi-
fication, and, thus, thyroid hormone synthesis. This is
known as the Wolff-Chaikoff effect.5
LABORATORY DIAGNOSIS
Subclinical hypothyroidism is primarily a laboratory diag-
nosis, and most patients have no symptoms or very mild
ones. Therefore, many patients will be detected based on
risk factors and screenings. With the exception of neonates,
however, the guidelines for screening the general population
without risk factors vary between experts. The American
Thyroid Association (ATA) recommends screening for
hypothyroidism starting at age 35 years, with repeat
screening every 5 years; the US Preventive Services Task
Force does not recommend screening at any age for hypo-
thyroidism in asymptomatic adults.6,7 Several medical
conditions are known to be associated with hypothyroid-
ism, including atrial fibrillation, type 1 diabetes, hyperlip-
idemia, breast cancer, and Down syndrome.8 Screening in
these populations could lead to earlier detection and
treatment of subclinical hypothyroidism, but there are no
firm recommendations about screening frequency.
22 www.JAAPA.com
Copyright © 2020 American Academy of Physician Assistants
h TSH ± symptoms
(fatigue, cold intolerance, weight gain,
bradycardia, constipation, dry skin, brittle hair/
nails, periorbital edema, or depression)
Check free T4
Normal free T4 iFree T4
Repeat TSH
Primary hypothyroidism
in 3 months
Still increased
Subclinical hypothyroidism
FIGURE 1. Differentiating overt (primary) from subclinical
hypothyroidism
The most accepted initial screening test for overt or
subclinical hypothyroidism is a serum TSH, as shown in
Figure 1. The normal range for TSH levels varies slightly,
but typically 0.4 to 4 mU/L is considered normal.9 In both
overt and subclinical hypothyroidism, the patient’s TSH
level is elevated. If TSH is elevated, the next step is to order
a free thyroxine (FT4) level. A FT4 below the average
normal range of 0.6 to 1.6 ng/dL is diagnostic of overt
hypothyroidism; one within the normal range is consistent
with subclinical hypothyroidism.10 A notable exception to
this is central hypothyroidism, which occurs with damage
to the pituitary-hypothalamic axis.11 In these patients, TSH
will be low to normal, with a low FT4.11 Additional thyroid-
specific laboratory tests may include anti-TPO antibodies,
which can distinguish the cause of the hypothyroidism as
Hashimoto thyroiditis.2 For patients with subclinical
hypothyroidism, anti-TPO antibodies are not routinely
obtained unless the decision to treat is in question. The
presence of anti-TPO antibodies supports treatment, as
they suggest an increased risk of progression from sub-
clinical to overt disease.12
If the patient’s symptoms are refractory to treatment, a
serum triiodothyronine (FT3) value can be obtained to
determine if a conversion problem exists for patients with
overt hypothyroidism.13 An FT3 does not provide much
value in the diagnosis of subclinical hypothyroidism because
these patients mostly present as asymptomatic.4
Other associated laboratory tests include a complete
blood cell (CBC) count and comprehensive metabolic
panel (CMP), which may reveal other conditions that
Volume 33 • Number 5 • May 2020

would explain a patient’s symptoms, including anemia,
hyponatremia, or hypoglycemia.9 A lipid panel and
creatine kinase also are warranted because of the effects
of thyroid hormones on lipid metabolism and muscles.
Hypothyroidism rarely requires imaging, but ultraso-
nography will be useful if thyroid nodules are present or
suspected.5
CLINICAL PRESENTATION AND ASSESSMENT
The clinical manifestations of subclinical hypothyroidism
often correlate to the patient’s TSH level.14 Most patients
with a TSH level less than 10 mU/L are asymptomatic.
Patients with a TSH greater than 10 mU/L may present with
the symptoms of overt hypothyroidism, which include
fatigue, cold intolerance, constipation, and weight gain.15
Other possible manifestations include coarse hair, hoarse-
ness, dry skin, brittle nails, periorbital edema, and depression.
Physical examination findings in a person with hypothy-
roidism also vary greatly depending on the severity of the
disease and the cause of the hypothyroidism.15 Most patients
with subclinical hypothyroidism present without abnormal
physical examination findings.14 If an abnormal finding is
present, it typically is a less-severe physical manifestation
of overt hypothyroidism. Some potential physical exami-
nation findings include brittle hair, macroglossia, hypohi-
drosis, peripheral or periorbital edema, facial puffiness,
neck goiter, bradycardia, muscle weakness, and delayed
ankle reflexes.16
DIFFERENTIAL DIAGNOSIS
The symptoms of hypothyroidism are vague, affect many
body systems, and manifest variably depending on disease
severity. Therefore, the differential diagnosis is extensive
and depends on the patient’s presenting symptoms. For
example, fatigue could also indicate anemia, obstructive
sleep apnea, depression, cancer, heart failure, infection,
fibromyalgia, or many other conditions. Additional symp-
toms of constipation, weight gain, dry skin, and cold
intolerance each have their own associated differential
diagnoses. If a patient presents with one or more of these
vague symptoms, obtain a TSH to exclude or include
hypothyroidism in the differential diagnosis.
Although diagnosis of subclinical hypothyroidism is
almost exclusively through laboratory findings, an isolated
elevation in TSH with a normal T4 level does not neces-
sarily provide a diagnosis of subclinical hypothyroidism.
Non-thyroid-related influences could temporarily raise the
TSH level, including obesity, moderate-to-severe chronic
kidney disease, and adrenal insufficiency. Body mass index
(BMI) correlates positively with TSH in patients who are
obese, and can normalize with weight loss. Other conditions
linked to causing elevations in TSH include recovering from
a non-thyroid-related illness and taking medications such
as amiodarone, amphetamine, and metoclopramide.17 About
35% of patients with an isolated elevation in TSH normal-
JAAPA Journal of the American Academy of PAs
Copyright © 2020 American Academy of Physician Assistants
Subclinical hypothyroidism: To treat or not to treat?
ize within 2 years.17 As a result, before beginning treatment
for subclinical hypothyroidism, obtain a repeat TSH level
in 3 months for patients with an isolated elevation in TSH;
a persistent elevation is consistent with the diagnosis of
subclinical hypothyroidism.18
CARDIOVASCULAR COMPLICATIONS
The associations between overt hypothyroidism and
cardiovascular complications have been thoroughly estab-
lished throughout the years.15 Hypothyroidism reduces
cardiac output and cardiac contractility, increases diastolic
BP, and disrupts lipid metabolism, specifically by elevat-
ing total cholesterol and low-density lipoprotein (LDL)
cholesterol.19
Hueston and Pearson concluded in their 2004 study of
8,228 total participants (215 with subclinical hypothyroid-
ism) that subclinical hypothyroidism was not associated
with cholesterol or triglyceride abnormalities after adjust-
ing for influencing variables.20 More recently, Hyland and
colleagues found no increased risk of coronary heart disease,
heart failure, or cardiovascular death in patients age 65
years and older with subclinical hypothyroidism.19
Levothyroxine is not
FDA-approved for the treatment
of subclinical hypothyroidism.
The number of studies supporting an association between
subclinical hypothyroidism and cardiovascular complica-
tions surpasses the number of studies that do not, however.
Two large retrospective studies (N = 13,915 and N =
17,046, respectively) performed by Meng and colleagues
and Zhao and colleagues in 2015 found a positive asso-
ciation between serum TSH, total cholesterol, and LDL
cholesterol.21,22 Zhao’s analysis estimated a 0.0147 mmol/L
increase in total cholesterol for every 1 mIU/L increase in
TSH in patients ages 40 to 49 years, and a 0.0551 mmol/L
increase in those ages 60 to 69 years.22 Additionally, a study
conducted in 2016 by Grossman and colleagues with
17,440 patients age 65 years and older determined an
increase in mortality in patients with a TSH greater than
6.38 mIU/L.23 Lastly, a meta-analysis performed by Moon
and colleagues in 2017 consisting of 555,530 patients from
35 studies concluded that subclinical hypothyroidism was
associated with CVD and mortality, especially in patients
with high CVD risks.24 However, the association was not
observed in patients age 65 years or older, contradicting
the results of Grossman and colleagues and supporting the
results of Hyland and colleagues.24 Given the evidence in
these large, recent studies, the relationship between sub-
clinical hypothyroidism and CVD is relatively well estab-
www.JAAPA.com 23
CME
lished. Whether treatment will reduce this risk remains a
question.
TREATMENT
Recommended treatment for all patients with overt hypo-
thyroidism is levothyroxine, a synthetic thyroid hormone.18
The starting dose for younger patients without CVD is 1.6
mcg/kg/day. Lower starting doses of 12.5 to 25 mcg/day
with gradual dose increases are recommended for older
adults and patients with CVD.25 In all patients, the levo-
thyroxine dose should be adjusted based on the TSH level.
TSH levels should be monitored every 6 to 8 weeks after
a levothyroxine dose change to confirm a therapeutic TSH
value. The target TSH range for patients age 70 years and
younger is 0.5 to 2.5 mU/L, and 1 to 5 mU/L for patients
age 65 to 70 years.5 Once a therapeutic TSH is achieved,
monitor the patient’s TSH level every 6 to 12 months.25
Treatment for patients with subclinical hypothyroidism
is much less well defined. Levothyroxine is not FDA-
approved for the treatment of subclinical hypothyroidism,
although it is the standard of care for those who are to be
treated. Per the 2012 ATA/American Association of Clin-
ical Endocrinologists’ clinical guidelines for hypothyroid-
ism in adults (and reaffirmed by the ATA in its 2014
guidelines), it is always recommended to treat anyone with
a TSH greater than 10 mU/L.6,26 For patients with elevated
TSH that is less than 10 mU/L, other factors need to be
considered, as shown in Table 1. Unfortunately, the research
that has been conducted since the publication of these
guidelines has not further clarified the issue. Studies about
symptoms, quality of life, and cardiovascular risk still show
conflicting results.
A 2016 cohort study conducted by Winther and col-
leagues with 78 patients concluded that 6 months of
levothyroxine therapy improved the health-related quality
of life in patients with autoimmune overt and subclinical
hypothyroidism.27 Conversely, the much larger placebo-
controlled TRUST trial by Stott and colleagues, consisting
of 737 adults with subclinical hypothyroidism, concluded
that levothyroxine did not provide any symptomatic ben-
efits in patients with subclinical hypothyroidism.28 Although
this trial was one of the largest studies to evaluate symp-
tomatic improvement with levothyroxine treatment in
patients with subclinical hypothyroidism, it was limited
because the initial severity of symptoms was mild, and
most patients were asymptomatic. Consequently, no
improvement would have necessarily been expected with
treatment.
An additional follow-up study to the TRUST trial con-
ducted by Blum and colleagues evaluated 185 participants
from the original trial to determine if treatment with levo-
thyroxine in patients with subclinical hypothyroidism
resulted in any improvement on two markers for stroke
risk, carotid intima-media thickness and carotid plaque
burden.29 The study concluded that the normalization of
24 www.JAAPA.com
Copyright © 2020 American Academy of Physician Assistants
TABLE 1. Benefits vs. risks of treatment for
subclinical hypothyroidism6,19,25
Patients most likely to benefit
• Those under age 70 years
• Women who are pregnant
• Women who are infertile
• Those with a symptomatic goiter
• Those who are anti-TPO positive
• Those at high risk for CVD
Significant risks of treatment
Worsening of:
• Tachycardia
• Atrial fibrillation
• Heart failure
• Angina
• Fracture risks (preexisting osteoporosis, chronic steroids, or
antiepileptic drugs)
• Untreated psychologic conditions
• Severe anemia
TSH with levothyroxine treatment did not affect carotid
intima-media thickness and carotid plaque burden, but
these parameters were not measured before the start of the
trial and could have initially measured minimal to none.
The Blum study directly conflicts with a meta-analysis
performed by Zhao and colleagues in 2017 of nine publica-
tions (247 patients with subclinical hypothyroidism), the
results of which showed a decrease in carotid intima-media
thickness with levothyroxine treatment compared with
measurements before treatment.30 Further supporting treat-
ment of subclinical hypothyroidism in relation to cardio-
vascular risk factors, a 2017 meta-analysis by Abreu and
colleagues evaluated the effects of levothyroxine treatment
on lipid profiles in patients with subclinical hypothyroid-
ism.31 The analysis of five studies and 253 patients found
a significant decrease in total cholesterol and LDL choles-
terol in the patients treated with levothyroxine compared
with the placebo groups. However, Andersen and colleagues
concluded in 2016 after retrospective evaluation of 61,611
patients with established heart disease that treatment of
subclinical hypothyroidism with levothyroxine did not
reduce mortality, hospital admissions, or major adverse
cardiac reactions.32 This study did not evaluate additional
individual risk factors contributing to cardiac outcomes
and did not have specific information about treatment,
including treatment length and treatment adherence.
COMPLICATIONS OF TREATMENT
Studies have shown that about 40% of patients with overt
hypothyroidism may be overtreated.18 Another 40% fail
to reach therapeutic TSH levels even with treatment.19 This
variability can be attributed, in part, to medication admin-
istration issues. For optimal and consistent absorption,
Volume 33 • Number 5 • May 2020

levothyroxine must be taken on an empty stomach, either
30 to 60 minutes before or 3 to 4 hours after the intake of
any food or beverage.25 Many significant drug interactions
can alter levothyroxine absorption, affecting its effective-
ness and adverse reactions. Levothyroxine also has a very
long half-life and takes 6 weeks or more to reach steady
state. During this time, patients may have continuing
symptoms; conversely, the recommended weight-based
dosing may overestimate the appropriate dose initially if
not based on lean body weight, putting patients at greater
risk for adverse reactions. Levothyroxine may worsen the
conditions shown in Table 1.19,25 The TRUST trial showed
no difference in adverse reactions (including atrial fibril-
lation, heart failure, fracture, or osteoporosis) between
older patients treated with levothyroxine for subclinical
hypothyroidism and those treated with placebo.28
FOLLOW-UP
The progression rate to overt hypothyroidism is 2.6%
yearly in patients who do not have TPO antibodies and
4.3% yearly in those with TPO antibodies.33 Treatment of
subclinical hypothyroidism may halt or slow the progres-
sion to overt hypothyroidism, but there is no evidence to
support this effect.33 Patients must continue to have TSH
monitored at least yearly and be educated to report symp-
toms or adverse reactions.
Hypothyroidism typically can be diagnosed and managed
by a primary care clinician; however, an endocrinologist
referral may be warranted in certain cases. For example,
refer patients if the diagnosis or cause is uncertain, if the
patient has a past medical history of thyroid disease or has
a goiter, or if the patient is pregnant or wishes to become
pregnant.17
CONCLUSION
Although subclinical hypothyroidism affects a significant
portion of the population, guidelines for treating it remain
unclear due to a lack of consistency in related studies.
Current recommendations are to treat all patients with a
TSH greater than 10 mU/L, as well as those with a TSH
less than 10 mU/L who are under age 70 years, are preg-
nant, are infertile, are experiencing symptoms of hypothy-
roidism, have a goiter, have anti-TPO antibodies, or have
elevated CVD risk.21 Other patients also may benefit from
treatment, and the decision to initiate levothyroxine ther-
apy is left to the clinician. At this time, more studies appear
to support an association between subclinical hypothyroid-
ism and cardiovascular risk factors, thus supporting treat-
ment in order to reduce these risks. Clinicians must
compare risks of levothyroxine treatment with the poten-
tial advantages, including this reduction in CVD risk and
possible symptomatic improvement.
For the case patient, as a relatively healthy 65-year-old
woman with a first-degree relative with CVD, the advan-
tages of treatment likely outweigh the risks, although her
JAAPA Journal of the American Academy of PAs
Copyright © 2020 American Academy of Physician Assistants
Subclinical hypothyroidism: To treat or not to treat?
symptoms are minimal. However, more information on
her health status and history are warranted, specifically
her bone-mineral density or FRAX score. Ultimately, more
conclusive studies addressing the symptomatic or cardio-
vascular benefits from levothyroxine therapy, and studies
comparing the long-term effects of subclinical hypothyroid-
ism in both observed and treated patients could help
establish definitive treatment guidelines. JAAPA
Earn Category I CME Credit by reading both CME articles in this
issue, reviewing the post-test, then taking the online test at http://
cme.aapa.org. Successful completion is defined as a cumulative
score of at least 70% correct. This material has been reviewed and is
approved for 1 hour of clinical Category I (Preapproved) CME credit
by the AAPA. The term of approval is for 1 year from the publication
date of May 2020.
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Volume 33 • Number 5 • May 2020