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ORIGINAL STUDIES, REVIEWS,AND SCHOLARLY DIALOG
THYROID FUNCTION AND DYSFUNCTION
Clinical Practice Guidelines for Hypothyroidism in
Adults:Cosponsored by the American Association of
ClinicalEndocrinologists and the American Thyroid Association
Jeffrey R. Garber,1,2,* Rhoda H. Cobin,3 Hossein Gharib,4 James
V. Hennessey,2 Irwin Klein,5
Jeffrey I. Mechanick,6 Rachel Pessah-Pollack,6,7 Peter A.
Singer,8 and Kenneth A. Woeber9
for the American Association of Clinical Endocrinologists and
American Thyroid AssociationTaskforce on Hypothyroidism in
Adults
Background: Hypothyroidism has multiple etiologies and
manifestations. Appropriate treatment requires anaccurate diagnosis
and is influenced by coexisting medical conditions. This paper
describes evidence-basedclinical guidelines for the clinical
management of hypothyroidism in ambulatory patients.Methods: The
development of these guidelines was commissioned by the American
Association of Clinical En-docrinologists (AACE) in association
with American Thyroid Association (ATA). AACE and the ATA assembled
atask force of expert clinicians who authored this article. The
authors examined relevant literature and took anevidence-based
medicine approach that incorporated their knowledge and experience
to develop a series ofspecific recommendations and the rationale
for these recommendations. The strength of the recommendations
andthe quality of evidence supporting each was rated according to
the approach outlined in the American Associationof Clinical
Endocrinologists Protocol for Standardized Production of Clinical
Guidelines2010 update.Results: Topics addressed include the
etiology, epidemiology, clinical and laboratory evaluation,
management,and consequences of hypothyroidism. Screening, treatment
of subclinical hypothyroidism, pregnancy, and areasfor future
research are also covered.Conclusions: Fifty-two evidence-based
recommendations and subrecommendations were developed to aid inthe
care of patients with hypothyroidism and to share what the authors
believe is current, rational, and optimalmedical practice for the
diagnosis and care of hypothyroidism. A serum thyrotropin is the
single best screeningtest for primary thyroid dysfunction for the
vast majority of outpatient clinical situations. The standard
treat-ment is replacement with L-thyroxine. The decision to treat
subclinical hypothyroidism when the serum thy-rotropin is less than
10mIU/L should be tailored to the individual patient.
By mutual agreement among the authors and the editors of their
respective journals, this work is being published jointly in
Thyroid andEndocrine Practice.
*Jeffrey R. Garber, M.D., is Chair of the American Association
of Clinical Endocrinologists and American Thyroid Association
Taskforce onHypothyroidism in Adults. All authors after the first
author are listed in alphabetical order.
1Endocrine Division, Harvard Vanguard Medical Associates,
Boston, Massachusetts.2Division of Endocrinology, Beth Israel
Deaconess Medical Center, Boston, Massachusetts.3New Jersey
Endocrine and Diabetes Associates, Ridgewood, New Jersey.4Division
of Endocrinology, Mayo Clinic, Rochester, Minnesota.5The Thyroid
Unit, North Shore University Hospital, Manhassett, New
York.6Division of Endocrinology, Mount Sinai Hospital, New York,
New York.7Division of Endocrinology, ProHealth Care Associates,
Lake Success, New York.8Keck School of Medicine, University of
Southern California, Los Angeles, California.9UCSF Medical Center
at Mount Zion, San Francisco, California.
THYROIDVolume 22, Number 12, 2012 Mary Ann Liebert, Inc.DOI:
10.1089/thy.2012.0205
1200
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INTRODUCTION
These updated clinical practice guidelines (CPGs)(13) summarize
the recommendations of the authors,acting as a joint American
Association of Clinical En-docrinologists (AACE) and American
Thyroid Association(ATA) task force for the diagnostic evaluation
and treatmentstrategies for adults with hypothyroidism, as mandated
by theBoard of Directors of AACE and the ATA.
The ATA develops CPGs to provide guidance and recom-mendations
for particular practice areas concerning thyroiddisease, including
thyroid cancer. The guidelines are not in-clusive of all proper
approaches or methods, or exclusive ofothers. the guidelines do not
establish a standard of care, andspecific outcomes are not
guaranteed. Treatment decisionsmustbe made based on the independent
judgment of health careproviders and each patients individual
circumstances. Aguideline is not intended to take the place of
physician judgmentin diagnosing and treatment of particular
patients (for detailedinformation regarding ATA guidelines, see the
SupplementaryData, available online at www.liebertpub.com/thy).
The AACE Medical Guidelines for Clinical Practice
aresystematically developed statements to assist health
careprofessionals in medical decision making for specific
clinicalconditions. Most of their content is based on literature
re-views. In areas of uncertainty, professional judgment is
ap-plied (for detailed information regarding AACE guidelines,see
the Supplementary Data).
These guidelines are a document that reflects the currentstate
of the field and are intended to provide a working doc-ument for
guideline updates since rapid changes in this fieldare expected in
the future. We encourage medical profession-als to use this
information in conjunction with their bestclinical judgment. The
presented recommendations may notbe appropriate in all situations.
Any decision by practitioners
to apply these guidelines must be made in light of local
re-sources and individual patient circumstances.
The guidelines presented here principally address themanagement
of ambulatory patients with biochemicallyconfirmed primary
hypothyroidism whose thyroid status hasbeen stable for at least
several weeks. They do not deal withmyxedema coma. The interested
reader is directed to the othersources for this information (4).
The organization of theguidelines is presented in Table 1.
Serum thyrotropin (TSH) is the single best screening test
forprimary thyroid dysfunction for the vast majority of
outpatientclinical situations, but it is not sufficient for
assessing hospital-ized patients or when central hypothyroidism is
either presentor suspected. The standard treatment is replacement
withL-thyroxine which must be tailored to the individual
patient.The therapy and diagnosis of subclinical
hypothyroidism,which often remains undetected, is discussed.
L-triiodothyro-nine in combination with L-thyroxine for treating
hypo-thyroidism, thyroid hormone for conditions other
thanhypothyroidism, and nutraceuticals are considered.
METHODS
This CPG adheres to the 2010 AACE Protocol for Stan-dardized
Production of Clinical Practice Guidelines publishedin Endocrine
Practice (5). This updated protocol describes amore transparent
methodology of rating the clinical evidenceand synthesizing
recommendation grades. The protocol alsostipulates a rigorous
multilevel review process.
The process was begun by developing an outline for re-viewing
the principal clinical aspects of hypothyroidism.Computerized and
manual searches of the medical literatureand various databases,
primarily including Medline, werebased on specific section titles,
thereby avoiding inclusion ofunnecessary detail and exclusion of
important studies.
Table 1. Organization of Clinical Practice Guidelines for
Hypothyroidism in Adults
Page
Introduction 1201Methods 1201Objectives 1204Guidelines for CPGs
1204Levels of scientific substantiation and recommendation grades
(transparency) 1204Summary of recommendation grades 1205
Topics Relating to Hypothyroidism 1205Epidemiology 1205Primary
and secondary etiologies of hypothyroidism 1206Disorders associated
with hypothyroidism 1207Signs and symptoms of hypothyroidism
1207Measurement of T4 and T3 1207Pitfalls encountered when
interpreting serum TSH levels 1208Other diagnostic tests for
hypothyroidism 1209Screening and aggressive case finding for
hypothyroidism 1209When to treat hypothyroidism 1210L-thyroxine
treatment of hypothyroidism 1210Therapeutic endpoints in the
treatment of hypothyroidism 1213When to consult an endocrinologist
1214Concurrent conditions of special significance in hypothyroid
patients 1214Hypothyroidism during pregnancy 1214Diabetes mellitus
1215Infertility 1215
(continued)
PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS 1201
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Table 1. (Continued)
Page
Obesity 1215Patients with normal thyroid tests 1215Depression
1215Nonthyroidal illness 1215
Dietary supplements and nutraceuticals in the treatment of
hypothyroidism 1216Overlap of symptoms in euthyroid and hypothyroid
patients 1216Excess iodine intake and hypothyroidism 1216Desiccated
thyroid 12163,5,3-Triiodothyroacetic acid 1217Thyroid-enhancing
preparations 1217Thyromimetic preparations 1217Selenium 1217
Questions and Guideline Recommendations 1217Q1 When should
anti-thyroid antibodies be measured? 1217R1 TPOAb measurements and
subclinical hypothyroidism 1217R2 TPOAb measurements and nodular
thyroid disease 1217R3 TPOAb measurements and recurrent miscarriage
1217R4 TSHRAb measurements in women with Graves disease who
have
had thyroidectomy or RAI treatment before pregnancy1217
Q2 What is the role of clinical scoring systems in the diagnosis
of patientswith hypothyroidism?
1218
R5 Do not use clinical scoring systems to diagnose
hypothyroidism 1218Q3 What is the role of diagnostic tests apart
from serum thyroid hormone levels and TSH in
the evaluation of patients with hypothyroidism?1218
R6 Do not use indirect tests to diagnose hypothyroidism 1218Q4
What are the preferred thyroid hormone measurements in addition to
TSH in the assessment of
patients with hypothyroidism?1218
R7 When to use free T4 vs. total T4 1218R8 Using free T4 to
monitor L-thyroxine treatment 1218R9 Estimating serum free T4 in
pregnancy 1218R10 Prohibition against using T3 to diagnose
hypothyroidism 1218R11 Measuring TSH in hospitalized patients
1218R12 Serum T4 vs. TSH for management of central hypothyroidism
1218Q5 When should TSH levels be measured in patients being treated
for hypothyroidism? 1218R13 When to measure TSH in patients taking
L-thyroxine for hypothyroidism 1218Q6 What should be considered the
upper limit of the normal range of TSH values? 1218R14.1 Reference
ranges for TSH, age, and lab variability 1218R14.2 Reference ranges
for TSH in pregnant women 1218Q7 Which patients with TSH levels
above a given laboratorys reference range should be considered
for
treatment with L-thyroxine?1219
R15 Treating patients with TSH above 10mIU/L 1219R16 Treating if
TSH is elevated but below 10mIU/L 1219Q8 In patients with
hypothyroidism being treated with L-thyroxine what should the
target TSH
ranges be?1219
R17 Target TSH when treating hypothyroidism 1219Q9 In patients
with hypothyroidism being treated with L-thyroxine who are
pregnant, what should the
target TSH ranges be?1219
R18 Target TSH when treating hypothyroid pregnant women 1219Q10
Which patients with normal serum TSH levels should be considered
for treatment with
L-thyroxine?1219
R19.1 L-thyroxine treatment in pregnant women with normal TSH
1219R19.2 L-thyroxine treatment in women of child-bearing age or
pregnant with normal TSH
and have positive TPOAb or history of miscarriage or
hypothyroidism1219
R19.3 L-thyroxine treatment in pregnant women or those planning
pregnancy with TPOAband serum TSH is > 2.5mIU/L
1219
R19.4 Monitoring of pregnant women with TPOAb or a normal TSH
but > 2.5mIU/Lwho are not taking L-thyroxine
1219
Q11 Who, among patients who are pregnant, or planning pregnancy,
or with other characteristics,should be screened for
hypothyroidism?
1220
R20.1.1 Universal screening of women planning pregnancy included
assisted reproduction 1220R20.1.2 Aggressive case finding for
hypothyroidism for women planning pregnancy 1220R20.2 Age and
screening for hypothyroidism 1220
(continued)
1202 GARBER ET AL.
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Table 1. (Continued)
Page
R21 Aggressive case finding for hypothyroidismwhom to target
1220Q12 How should patients with hypothyroidism be treated and
monitored? 1220R22.1 Form of thyroid hormone for treatment of
hypothyroidism 1220R22.2 L-thyroxine and L-triiodothyronine
combinations to treat hypothyroidism 1220R22.3 Prohibition against
using L-thyroxine and L-triiodothyronine combinations
to treat pregnant women or those planning pregnancy1220
R22.4 Prohibition against using desiccated thyroid hormone to
treat hypothyroidism 1220R22.5 Prohibition against using TRIAC
(tiratricol) to treat hypothyroidism 1220R22.6 Resuming L-thyroxine
treatment for hypothyroidism in patients without cardiac events
1220R22.7.1 L-thyroxine treatment for overt hypothyroidism in young
healthy adults 1220R22.7.2 L-thyroxine treatment for overt
hypothyroidism in patients older than 50 to 60 years 1220R22.8
L-thyroxine treatment for subclinical hypothyroidism compared to
overt
hypothyroidism1220
R22.9 Order of L-thyroxine treatment and glucocorticoids in
patients with adrenalinsufficiency and hypothyroidism
1221
R23 L-thyroxine treatment for hypothyroidismtime to take, method
of taking,and storage
1221
R24 Free T4 as the target measurement when treating central
hypothyroidism 1221R25.1 Testing and treating women with
hypothyroidism as soon as they become pregnant 1221R25.2 Goal TSH
in pregnant women with hypothyroidism 1221R25.3 Monitoring pregnant
women with hypothyroidism 1221R26 Monitoring hypothyroid patients
who start drugs affecting T4 bioavailability
or metabolism1221
R27 Prohibition against targeting specific TSH values in
hypothyroid patients who arenot pregnant
1221
Q13 When should endocrinologists be involved in the care of
patients with hypothyroidism? 1221R28 Type of hypothyroid patient
who should be seen in consultation with
an endocrinologist1221
Q14 Which patients should not be treated with thyroid hormone?
1221R29 Need for biochemical confirmation of the diagnosis before
chronic treatment
of hypothyroidism1221
R30 Prohibition against using thyroid hormone to treat obesity
1221R31 Thyroid hormone treatment and depression 1222Q15 What is
the role of iodine supplementation, dietary supplements, and
nutraceuticals
in the treatment of hypothyroidism?1222
R32.1 Prohibition against using iodine supplementation to treat
hypothyroidismin iodine-sufficient areas
1222
R32.2 Inappropriate method for iodine supplementation in
pregnant women 1222R33 Prohibition against using selenium as
treatment or preventive measure
for hypothyroidism1222
R34 Recommendation regarding dietary supplements,
nutraceuticals,and products marked as thyroid support for
hypothyroidism
1222
Areas for Future Research 1222Cardiac benefit from treating
subclinical hypothyroidism 1222Cognitive benefit from treating
subclinical hypothyroidism 1223L-thyroxine/L-triiodothyronine
combination therapy 1223L-triiodothyronine monotherapy 1223Thyroid
hormone analogues 1223Screening for hypothyroidism in pregnancy
1223Agents and conditions having an impact on L-thyroxine therapy
and interpretation
of thyroid tests1223
Author Disclosure Statement 1224Acknowledgments 1224References
including authors evidence level (EL) rankings 1224Supplementary
Data Online at www.liebertpub.com/thy1. Supplementary information
regarding ATA and AACE guidelines2. Complete list of guideline
recommendations
Note: When referring to therapy and therapeutic preparations in
the recommendations and elsewhere, L-thyroxine and
L-triiodothyronineare generally used instead of their respective
hormonal equivalents, T4 and T3.AACE, American Association of
Clinical Endocrinologists; ATA, American Thyroid Association; CPG,
Clinical Practice Guideline; RAI,
radioactive iodine; T3, triiodothyronine; T4, thyroxine; TPOAb,
antithyroid peroxidase antibodies; TRIAC, 3,5,3-triiodothyroacetic
acid;TSH, thyrotropin; TSHRAb, TSH receptor antibodies.
PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS 1203
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Compilation of the bibliographywas a continual and
dynamicprocess. Once the principal clinical aspects of
hypothyroidismwere defined, questions were formulated with the
intent tothen develop recommendations that addressed these
ques-tions. The grading of recommendations was based on con-sensus
among the authors.
The final document was approved by the American Asso-ciation of
Clinical Endocrinologists (AACE) and AmericanThyroid Association
(ATA), and was officially endorsed bythe American Association of
Diabetes Educators (AADE),AmericanAssociationof Endocrine Surgeons
(AAES),AmericanAcademy of OtolaryngologyHead and Neck Surgery
(AAO-HNS), American College of Endocrinology (ACE),
ItalianAssociation of Clinical Endocrinologists (AME), American
So-ciety forMetabolic & Bariatric Surgery (ASMBS), The
EndocrineSociety of Australia (ESA), International Association of
Endo-crine Surgeons (IAES), Korean Thyroid Association (KTA),Latin
American Thyroid Society (LATS), and Ukranian Asso-ciation of
Endocrine Surgeons (UAES).
Objectives
The purpose of these guidelines is to present an
updatedevidence-based framework for the diagnosis, treatment,
andfollow-up of patients with hypothyroidism.
Guidelines for CPGs
Current guidelines for CPGs in clinical medicine emphasizean
evidence-based approach rather than simply expert opin-
ion (6). Even though a purely evidence-based approach is
notapplicable to all actual clinical scenarios, we have
incorpo-rated this into these CPGs to provide objectivity.
Levels of scientific substantiation andrecommendation grades
(transparency)
All clinical data that are incorporated in these CPGs havebeen
evaluated in terms of levels of scientific substantiation.The
detailed methodology for assigning evidence levels(ELs) to the
references used in these CPGs has been reportedby Mechanick et al.
(7), from which Table 2 is taken. Theauthors EL ratings of the
references are included in theReferences section. The four-step
approach that the authorsused to grade recommendations is
summarized in Tables 3,4, 5, and 6 of the 2010 Standardized
Production of ClinicalPractice Guidelines (5), from which Table 3
is taken. Byexplicitly providing numerical and semantic
descrip-tors of the clinical evidence as well as relevant
subjectivefactors and study flaws, the updated protocol has
greatertransparency than the 2008 AACE protocol described
byMechanick et al. (7).
In these guidelines, the grading system used for the
rec-ommendations does not reflect the instruction of the
recom-mendation, but the strength of the recommendation. Forexample
in some grading systems should not implies thatthere is substantial
evidence to support a recommendation.However the grading method
employed in this guideline
Table 2. Levels of Scientific Substantiation in Evidence-Based
Medicine
Level Description Comments
1 Prospective, randomized, controlledtrialslarge
Data are derived from a substantial number of trials with
adequatestatistical power involving a substantial number of outcome
datasubjects.
Large meta-analyses using raw or pooled data or
incorporatingquality ratings
Well-controlled trial at one or more centersConsistent pattern
of findings in the population for which therecommendation is made
(generalizable data).
Compelling nonexperimental, clinically obvious, evidence (e.g.,
thyroidhormone treatment for myxedema coma), all-or-none
indication
2 Prospective controlled trials with orwithout
randomizationlimitedbody of outcome data
Limited number of trials, small population sites in
trialsWell-conducted single-arm prospective cohort studyLimited but
well-conducted meta-analysesInconsistent findings or results not
representative for the targetpopulation
Well-conducted case-controlled study3 Other experimental
outcome
data and nonexperimental dataNonrandomized, controlled
trialsUncontrolled or poorly controlled trialsAny randomized
clinical trial with one or more major or threeor more minor
methodological flaws
Retrospective or observational dataCase reports or case
seriesConflicting data with weight of evidence unable to supporta
final recommendation
4 Expert opinion Inadequate data for inclusion in level 1, 2, or
3; necessitatesan expert panels synthesis of the literature and a
consensus
Experience basedTheory driven
Levels 1, 2, and 3 represent a given level of scientific
substantiation or proof. Level 4 or Grade D represents unproven
claims. It is the bestevidence based on the individual ratings of
clinical reports that contributes to a final grade
recommendation.Source: Mechanick et al., 2008 (7).
1204 GARBER ET AL.
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enables authors to use this language even when the best
evi-dence level available is expert opinion. Although
differentgrading systems were employed, an effort was made to
makethese recommendations consistent with related portions
ofHyperthyroidism and Other Causes of Thyrotoxicosis:Management
Guidelines of the American Thyroid Associa-tion and American
Association of Clinical Endocrinologists(8,9), as well as the
Guidelines of the American ThyroidAssociation for the Diagnosis and
Management of ThyroidDisease During Pregnancy and Postpartum
(10).
The shortcomings of this evidence-based methodology inthese CPGs
are that many recommendations are based onweak scientific data
(Level 3) or consensus opinion (Level 4),rather than strong
scientific data (Levels 1 and 2). There arealso the problems of (i)
subjectivity on the part of the authorswhen weighing positive and
negative, or epidemiologicversus experimental, data in order to
arrive at an evidence-
based recommendation grade or consensus opinion, (ii)
sub-jectivity on the part of the authors when weighing
subjectiveattributes, such as cost effectiveness and
risk-to-benefit ratios,in order to arrive at an evidence-based
recommendationgrade or consensus opinion, (iii) potentially
incomplete re-view of the literature by the authors despite
extensive dili-gence, and (iv) bias in the available publications,
whichoriginate predominantly from experienced clinicians andlarge
academic medical centers andmay, therefore, not reflectthe
experience at large. The authors, through an a priorimethodology
and multiple levels of review, have tried toaddress these
shortcomings by discussions with three experts(see
Acknowledgments).
Summary of recommendation grades
The recommendations are evidence-based (Grades A, B, andC) or
based on expert opinion because of a lack of conclusiveclinical
evidence (Grade D). The best evidence rating level(BEL), which
corresponds to the best conclusive evidencefound, accompanies the
recommendation grade. Details re-garding the mapping of clinical
evidence ratings to these rec-ommendation grades have already been
provided [see Levels ofscientific substantiation and recommendation
grades (transparen-cy)]. In this CPG, a substantial number of
recommendations areupgraded or downgraded because the conclusions
may notapply in other situations (non-generalizability). For
example,what applies to an elderly population with established
cardiacdiseasemay not apply to a younger populationwithout
cardiacrisk factors. Whenever expert opinions resulted in
upgradingor downgrading a recommendation, it is explicitly stated
afterthe recommendation.
TOPICS RELATING TO HYPOTHYROIDISM
Epidemiology
Hypothyroidism may be either subclinical or overt. Sub-clinical
hypothyroidism is characterized by a serum TSHabove the upper
reference limit in combination with a normalfree thyroxine (T4).
This designation is only applicable whenthyroid function has been
stable for weeks or more, the hy-pothalamicpituitarythyroid axis is
normal, and there is norecent or ongoing severe illness. An
elevated TSH, usuallyabove 10mIU/L, in combination with a subnormal
free T4characterizes overt hypothyroidism.
The results of four studies are summarized in Table 4.The
National Health and Nutrition Examination Survey(NHANES III)
studied an unselected U.S. population over age12 between 1988 and
1994, using the upper limit of normal for
Table 3. Grade-Recommendation Protocol
2010 AACE Protocol for Production of Clinical
PracticeGuidelinesStep III: Grading of recommendations;
How different evidence levels can be mappedto the same
recommendation grade
Bestevidencelevel
Subjectivefactorimpact
Two-thirds
consensus MappingaRecommendation
grade
1 None Yes Direct A2 Positive Yes Adjust up A2 None Yes Direct
B1 Negative Yes Adjust down B3 Positive Yes Adjust up B3 None Yes
Direct C2 Negative Yes Adjust down C4 Positive Yes Adjust up C4
None Yes Direct D3 Negative Yes Adjust down D1,2,3,4 N/A No Adjust
down D
Adopted by the AACE and the ATA for the Hypothyroidism
CPG.aStarting with the left column, best evidence levels
(BELs),
subjective factors, and consensus map to recommendation gradesin
the right column. When subjective factors have little or no
impact(none), then the BEL is directly mapped to
recommendationgrades. When subjective factors have a strong impact,
then recom-mendation grades may be adjusted up (positive impact) or
down(negative impact). If a two-thirds consensus cannot be
reached,then the recommendation grade is D.Source: Mechanick et
al., 2010 (5).N/A, not applicable (regardless of the presence or
absence of
strong subjective factors, the absence of a two-thirds
consensusmandates a recommendation grade D).
Table 4. Prevalence of Hypothyroidism
Study Subclinical Overt TSH Comment
NHANES III 4.3% 0.3% 4.5Colorado Thyroid Disease Prevalence 8.5%
0.4% 5.0 Not on thyroid hormoneFramingham 10.0 Over age 60 years:
5.9% women; 2.3% men; 39% of
whom had subnormal T4British Whickham 10.0 9.3% women; 1.2%
men
Sources: Hollowell et al., 2002 (11); Canaris et al., 2000 (12);
Sawin et al., 1985 (13); Vanderpump et al., 1995 (14); Vanderpump
andTunbridge, 2002 (15).NHANES, National Health and Nutrition
Examination Survey.
PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS 1205
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TSH as 4.5mIU/mL (11). The prevalence of subclinical dis-ease
was 4.3% and of overt disease was 0.3%. The Coloradothyroid disease
prevalence survey, in which self-selected in-dividuals attending a
health fair were tested and an uppernormal TSH value of 5.0mIU/L
was used, reported a prev-alence of 8.5% and 0.4% for subclinical
and overt disease,respectively, in people not taking thyroid
hormone (12). In theFramingham study, 5.9% of women and 2.3% of men
over theage of 60 years had TSH values over 10mIU/L, 39% of whomhad
subnormal T4 levels (13). In the British Whickham survey9.3% of
women and 1.2% of men had serum TSH values over10mIU/L (14,15). The
incidence of hypothyroidism inwomenwas 3.5 per 1000 survivors per
year and in men it was 0.6 per1000 survivors per year. The risk of
developing hypothy-roidism in women with positive antibodies and
elevated TSHwas 4% per year versus 2%3% per year in those with
eitheralone (14,15). In men the relative risk rose even more in
eachcategory, but the rates remained well below those of women.
Primary and secondary etiologiesof hypothyroidism
Environmental iodine deficiency is the most commoncause of
hypothyroidism on a worldwide basis (16). In areasof iodine
sufficiency, such as the United States, the mostcommon cause of
hypothyroidism is chronic autoimmunethyroiditis (Hashimotos
thyroiditis). Autoimmune thyroiddiseases (AITDs) have been
estimated to be 510 times morecommon in women than in men. The
ratio varies from seriesto series and is dependent on the
definition of disease,whether it is clinically evident or not. In
the Whickhamsurvey (14), for example, 5% of women and 1% of men
hadboth positive antibody tests and a serum TSH value > 6.This
form of AITD (i.e., Hashimotos thyroiditis, chronicautoimmune
thyroiditis) increases in frequency with age(11), and is more
common in people with other autoimmunediseases and their families
(1725). Goiter may or may notbe present.
AITDs are characterized pathologically by infiltration ofthe
thyroid with sensitized T lymphocytes and serologicallyby
circulating thyroid autoantibodies. Autoimmunity to thethyroid
gland appears to be an inherited defect in immunesurveillance,
leading to abnormal regulation of immune re-sponsiveness or
alteration of presenting antigen in the thyroid(26,27).
One of the keys to diagnosing AITDs is determiningthe presence
of elevated anti-thyroid antibody titerswhich include
anti-thyroglobulin antibodies (TgAb), antimicrosomal/thyroid
peroxidase antibodies (TPOAb), andTSH receptor antibodies (TSHRAb).
Many patients withchronic autoimmune thyroiditis are biochemically
euthyroid.However, approximately 75% have elevated
anti-thyroidantibody titers. Once present, these antibodies
generallypersist, with spontaneous disappearance occurring
infre-quently. Among the disease-free population in the
NHANESsurvey, tests for TgAb were positive in 10.4% and TPOAb
in11.3%. These antibodies were more common in women thanmen and
increased with age. Only positive TPOAb tests weresignificantly
associated with hypothyroidism (11). The pres-ence of elevated
TPOAb titers in patients with subclinicalhypothyroidism helps to
predict progression to overt hypo-thyroidism4.3% per year with
TPOAb vs. 2.6% per year
without elevated TPOAb titers (14,28). The higher risk
ofdeveloping overt hypothyroidism in TPOAb-positive patientsis the
reason that several professional societies and manyclinical
endocrinologists endorse measurement of TPOAbs inthose with
subclinical hypothyroidism.
In patients with a diffuse, firm goiter, TPOAb should bemeasured
to identify autoimmune thyroiditis. Since non-immunologically
mediated multinodular goiter is rarely as-sociated with destruction
of functioning tissue andprogression to hypothyroidism (29), it is
important to identifythose patients with the nodular variant of
autoimmune thy-roiditis in whom these risks are significant. In
some cases,particularly in those with thyroid nodules, fine-needle
aspi-ration (FNA) biopsy helps confirm the diagnosis and to
ex-clude malignancy. Also, in patients with
documentedhypothyroidism, measurement of TPOAb identifies the
cause.
In the presence of other autoimmune disease such astype 1
diabetes (20,21) or Addisons disease (17,18), chromo-somal
disorders such as Downs (30) or Turners syndrome(31), and
therapywith drugs such as lithium (3234), interferonalpha (35,36),
and amiodarone (37) or excess iodine ingestion(e.g., kelp) (3840),
TPOAb measurement may provide prog-nostic information on the risk
of developing hypothyroidism.
TSHRAb may act as a TSH agonist or antagonist (41).Thyroid
stimulating immunoglobulin (TSI) and/or thyro-tropin binding
inhibitory immunoglobulin (TBII) levels,employing sensitive assays,
should be measured in euthy-roid or L-thyroxinetreated hypothyroid
pregnant womenwith a history of Graves disease because they are
predictorsof fetal and neonatal thyrotoxicosis (42). Since the risk
forthyrotoxicosis correlates with the magnitude of elevation ofTSI,
and since TSI levels tend to fall during the second tri-mester, TSI
measurements are most informative when donein the early third
trimester. The argument for measurementearlier in pregnancy is also
based, in part, on determin-ing whether establishing a surveillance
program for ongo-ing fetal and subsequent neonatal thyroid
dysfunction isnecessary (43).
Hypothyroidism may occur as a result of radioiodine orsurgical
treatment for hyperthyroidism, thyroid cancer, orbenign nodular
thyroid disease and after external beam ra-diation for
nonthyroid-related head and neck malignancies,including lymphoma. A
relatively new pharmacologic causeof iatrogenic hypothyroidism is
the tyrosine kinase inhibitors,most notably sunitinib (44,45),
which may induce hypothy-roidism through reduction of glandular
vascularity and in-duction of type 3 deiodinase activity.
Central hypothyroidism occurs when there is
insufficientproduction of bioactive TSH (46,47) due to pituitary or
hy-pothalamic tumors (including craniopharyngiomas), inflam-matory
(lymphocytic or granulomatous hypophysitis) orinfiltrative
diseases, hemorrhagic necrosis (Sheehans syn-drome), or surgical
and radiation treatment for pituitary orhypothalamic disease. In
central hypothyroidism, serum TSHmay be mildly elevated, but
assessment of serum free T4 isusually low, differentiating it from
subclinical primary hy-pothyroidism.
Consumptive hypothyroidism is a rare condition that mayoccur in
patients with hemangiomata and other tumors inwhich type 3
iodothyronine deiodinase is expressed, resultingin accelerated
degradation of T4 and triiodothyronine (T3)(48,49).
1206 GARBER ET AL.
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Disorders associated with hypothyroidism
The most common form of thyroid failure has an autoim-mune
etiology. Not surprisingly, there is also an increasedfrequency of
other autoimmune disorders in this populationsuch as type 1
diabetes, pernicious anemia, primary adrenalfailure (Addisons
disease), myasthenia gravis, celiac disease,rheumatoid arthritis,
systemic lupus erythematosis (1725),and rarely thyroid lymphoma
(50).
Distinct genetic syndromes with multiple
autoimmuneendocrinopathies have been described, with some
over-lapping clinical features. The presence of two of the
threemajor characteristics is required to diagnose the syndrome
ofmultiple autoimmune endocrinopathies (MAEs). The defin-ing major
characteristics for type 1 MAE and type 2 MAE areas follows:
Type 1 MAE: Hypoparathyroidism, Addisons disease,and
mucocutaneous candidiasis caused by mutations inthe autoimmune
regulator gene (AIRE), resulting indefective AIRE protein (51).
Autoimmune thyroiditis ispresent in about 10%15% (52).
Type 2 MAE: Addisons disease, autoimmune thyroid-itis, and type
1 diabetes known as Schmidts syndrome(53).
When adrenal insufficiency is present, the diagnosis
ofsubclinical hypothyroidism should be deferred until
afterglucocorticoid therapy has been instituted because TSHlevels
may be elevated in the presence of untreated adrenalinsufficiency
and may normalize with glucocorticoid ther-apy (54,55) (see
L-thyroxine treatment of hypothyroidism).
Signs and symptoms of hypothyroidism
The well-known signs and symptoms of hypothyroidismtend to
bemore subtle than those of hyperthyroidism.Dry skin,cold
sensitivity, fatigue, muscle cramps, voice changes, andconstipation
are among the most common. Less commonlyappreciated and typically
associated with severe hypothy-roidism are carpal tunnel syndrome,
sleep apnea, pituitaryhyperplasia that can occur with orwithout
hyperprolactinemiaand galactorrhea, and hyponatremia that can occur
withinseveral weeks of the onset of profound hypothyroidism.
Al-though, for example, in the case of some symptoms such asvoice
changes subjective (12,56) and objective (57) measuresdiffer.
Several rating scales (56,58,59) have been used to assessthe
presence and, in some cases, the severity of hypothyroid-ism, but
have low sensitivity and specificity.While the exerciseof
calculating clinical scores has been largely superseded bysensitive
thyroid function tests, it is useful to have objectiveclinical
measures to gauge the severity of hypothyroidism.Early as well as
recent studies strongly correlate the degree ofhypothyroidism with
ankle reflex relaxation time, a measurerarely used in current
clinical practice today (60).
Normalization of a variety of clinical and metabolic endpoints
including resting heart rate, serum cholesterol, anxietylevel,
sleep pattern, and menstrual cycle abnormalities in-cluding
menometrorrhagia are further confirmatory findingsthat patients
have been restored to a euthyroid state (6165).Normalization of
elevated serum creatine kinase or othermuscle (66) or hepatic
enzymes following treatment ofhypothyroidism (67) are additional,
less well-appreciated andalso nonspecific therapeutic
endpoints.
Measurement of T4 and T3
T4 is bound to specific binding proteins in serum. Theseare
T4-binding globulin (TBG) and, to a lesser extent,transthyretin or
T4-binding prealbumin and albumin. Sinceapproximately 99.97% of T4
is protein-bound, levels ofserum total T4 will be affected by
factors that alter bindingindependent of thyroid disease (Table 5)
(68,69). Accord-ingly, methods for assessing (including estimating
andmeasuring) serum free T4, which is the metabolicallyavailable
moiety (70), have been developed, and assessmentof serum free T4
has now largely replaced measurement ofserum total T4 as a measure
of thyroid status. Thesemethods include the serum free T4 index,
which is derivedas the product of total T4 and a thyroid hormone
bindingratio, and the direct immunoassay of free T4 after
ultrafil-tration or equilibrium dialysis of serum or after addition
ofanti-T4 antibody to serum (71).
A subnormal assessment of serum free T4 serves to estab-lish a
diagnosis of hypothyroidism, whether primary, inwhich serum TSH is
elevated, or central, in which serum TSHis normal or low (46,47).
An assessment of serum free T4(Table 6) is the primary test for
detecting hypothyroidism inantithyroid drugtreated or surgical or
radioiodine-ablatedpatients with previous hyperthyroidism in whom
serum TSHmay remain low for many weeks to months.
Inmonitoring patientswith hypothyroidism on
L-thyroxinereplacement, blood for assessment of serum free T4
should becollected before dosing because the level will be
transientlyincreased by up to 20% after L-thyroxine administration
(72).In one small study of athyreotic patients, serum total T4
levelsincreased above baseline by 1 hour and peaked at 2.5
hours,while serum free T4 levels peaked at 3.5 hours and
remainedhigher than baseline for 9 hours (72).
In pregnancy, measurement of serum total T4 is re-commended over
direct immunoassay of serum free T4. Be-cause of alterations in
serum proteins in pregnancy, directimmunoassay of free T4 may yield
lower values based onreference ranges established with normal
nonpregnant sera.Moreover, many patients will have values below the
non-pregnant reference range in the third trimester, including
Table 5. Factors That Alter Thyroxineand Triiodothyronine
Binding in Serum
Increased TBG Decreased TBG Binding inhibitors
Inherited Inherited SalicylatesPregnancy Androgens
FurosemideNeonatal state Anabolic steroids Free fatty
acidsEstrogens Glucocorticoids PhenytoinHepatitis Severe illness
CarbamazepinePorphyria Hepatic failure NSAIDs (variable,
transient)Heroin NephrosisHeparinMethadone Nicotinic acid
Mitotane L-Asparaginase5-FluorouracilSERMS
(e.g.,tamoxifen,raloxifene)
Perphanazine
TBG, T4-binding globulin; SERMS, selective estrogen
receptormodulators; NSAIDs, nonsteroidal anti-inflammatory
drugs.
PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS 1207
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values obtained with equilibrium dialysis (73).
Finally,method-specific and trimester-specific reference ranges
fordirect immunoassay of free T4 have not been generally
es-tablished. By contrast, total T4 increases during the first
tri-mester and the reference range is *1.5-fold that of
thenonpregnant range throughout pregnancy (73,74).
As is the case with T4, T3 is also bound to serum
proteins,principally TBG, but to a lesser extent than T4,
*99.7%.Methods for assessing free T3 concentration by direct
immu-noassay have been developed and are in current use
(71).However, serum T3 measurement, whether total or free,
haslimited utility in hypothyroidism because levels are oftennormal
due to hyperstimulation of the remaining functioningthyroid tissue
by elevated TSH and to up-regulation of type 2iodothyronine
deiodinase (75). Moreover, levels of T3 are lowin the absence of
thyroid disease in patients with severe illnessbecause of reduced
peripheral conversion of T4 to T3 and in-creased inactivation of
thyroid hormone (76,77).
Pitfalls encountered when interpretingserum TSH levels
Measurement of serum TSH is the primary screening testfor
thyroid dysfunction, for evaluation of thyroid hormonereplacement
in patients with primary hypothyroidism, andfor assessment of
suppressive therapy in patients with follic-ular cellderived
thyroid cancer. TSH levels vary diurnally byup to approximately 50%
of mean values (78), with more re-cent reports indicating up to 40%
variation on specimensperformed serially during the same time of
day (79). Valuestend to be lowest in the late afternoon and highest
around thehour of sleep. In light of this, variations of serum TSH
valueswithin the normal range of up to 40%50% do not
necessarilyreflect a change in thyroid status.
TSH secretion is exquisitely sensitive to both minor in-creases
and decreases in serum free T4, and abnormal TSHlevels occur during
developing hypothyroidism and hyper-thyroidism before free T4
abnormalities are detectable (80).According to NHANES III (11), a
disease-free population,which excludes those who self-reported
thyroid disease orgoiter or who were taking thyroid medications,
the uppernormal of serum TSH levels is 4.5mIU/L. A reference
pop-ulation taken from the disease-free population composed ofthose
who were not pregnant, did not have laboratory evi-dence of
hyperthyroidism or hypothyroidism, did not havedetectable TgAb or
TPOAb, and were not taking estrogens,androgens, or lithium had an
upper normal TSH value of4.12mIU/L. This was further supported by
the HanfordThyroid Disease Study, which analyzed a cohort
without
evidence of thyroid disease, were seronegative for
thyroidautoantibodies, were not on thyroid medications, and
hadnormal thyroid ultrasound examinations (which did not dis-close
nodularity or evidence of thyroiditis) (81). This uppernormal
value, however, may not apply to iodine insufficientregions even
after becoming iodine sufficient for 20 years(82,83).
More recently (84) the NHANES III reference populationwas
further analyzed and normal ranges based on age, U.S.Office of
Management of Budget Race and Ethnicity cate-gories, and sex were
determined. These indicated the 97.5thpercentile TSH values as low
as 3.24 for African Americansbetween the ages of 30 and 39 years
and as high as 7.84 forMexican Americans 80 years of age. For every
10-year ageincrease after 3039 years, the 97.5th percentile of
serum TSHincreases by 0.3mIU/L. Body weight, anti-thyroid
antibodystatus, and urinary iodine had no significant impact on
theseranges.
The National Academy of Clinical Biochemists, however,indicated
that 95% of individuals without evidence of thyroiddisease have TSH
concentrations below 2.5mIU/L (85), and ithas been suggested that
the upper limit of the TSH referencerange be lowered to 2.5mIU/L
(86).Whilemany patients withTSH concentrations in this range do not
develop hypothy-roidism, those patients with AITD are much more
likely todevelop hypothyroidism, either subclinical or overt (87)
(seeTherapeutic endpoints in the treatment of hypothyroidism
forfurther discussion).
In individuals without serologic evidence of AITD, TSHvalues
above 3.0mIU/L occur with increasing frequency withage, with
elderly (> 80 years of age) individuals having a23.9% prevalence
of TSH values between 2.5 and 4.5mIU/L,and a 12% prevalence of TSH
concentrations above 4.5mIU/L(88). Thus, very mild TSH elevations
in older individuals maynot reflect subclinical thyroid
dysfunction, but rather be anormal manifestation of aging. The
caveat is that while thenormal TSH reference rangeparticularly for
some subpop-ulationsmay need to be narrowed (85,86), the normal
ref-erence rangemaywidenwith increasing age (84). Thus, not
allpatients who have mild TSH elevations are hypothyroid
andtherefore would not require thyroid hormone therapy.
There are other pitfalls in the interpretation of the serumTSH
because abnormal levels are observed in various non-thyroidal
states. Serum TSH may be suppressed in hospital-ized patients with
acute illness, and levels below 0.1mIU/L incombination with
subnormal free T4 estimates may be seen incritically ill patients,
especially in those receiving dopamineinfusions (89) or
pharmacologic doses of glucocorticoids (90).In addition, TSH levels
may increase to levels above normal,
Table 6. Assessment of Free Thyroxine
Test Method Comments
Free T4 index or freeT4 estimate
Product of total T4 and thyroid hormonebinding ratio or T3-resin
uptake
Normal values in pregnancy and with alterationsin TBG
binding;
Direct immunoassayof free T4
With physical separation using equilibriumdialysis or
ultrafiltration
Reduced values in pregnancy compared tononpregnant reference
ranges; normal values withalterations in TBG binding
Direct immunoassayof free T4
Without physical separation using anti-T4antibody
Reduced values in pregnancy compared tononpregnant reference
ranges; normal values withalterations in TBG binding
1208 GARBER ET AL.
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but generally below 20mIU/L during the recovery phasefrom
nonthyroidal illness (91). Thus, there are limitations toTSH
measurements in hospitalized patients and, therefore,they should be
only performed if there is an index of suspicionfor thyroid
dysfunction (76).
Serum TSH typically falls, but infrequently to below0.1mU/L,
during the first trimester of pregnancy due to thethyroid
stimulatory effects of human chorionic gonadotro-pin and returns to
normal in the second trimester (10) (seeTable 7).
TSH secretion may be inhibited by administration of
sub-cutaneous octreotide, which does not cause persistent
centralhypothyroidism (92), and by oral bexarotene, which
almostalways does (93). In addition, patients with anorexia
nervosamay have low TSH levels in combination with low levels
offree T4 (94), mimicking what may be seen in critically ill
pa-tients and in patients with central hypothyroidism due
topituitary and hypothalamic disorders.
Patients with nonfunctioning pituitary adenomas, withcentral
hypothyroidism, may have mildly elevated serumTSH levels, generally
not above 6 or 7mIU/L, due to se-cretion of bioinactive isoforms of
TSH (47). TSH levels mayalso be elevated in association with
elevated serum thyroidhormone levels in patients with resistance to
thyroid hor-mone (95). Heterophilic or interfering antibodies,
includinghuman antianimal (most commonly mouse)
antibodies,rheumatoid factor, and autoimmune anti-TSH antibodiesmay
cause falsely elevated serum TSH values (96). Lastly,adrenal
insufficiency, as previously noted in Disorders asso-ciated with
hypothyroidism, may be associated with TSH ele-vations that are
reversed with glucocorticoid replacement(54,55).
Other diagnostic tests for hypothyroidism
Prior to the advent of routine validated chemical mea-surements
of serum thyroid hormones and TSH, tests that
correlated with thyroid status, but not sufficiently specific
todiagnose hypothyroidism, were used to diagnose hypothy-roidism
and to gauge the response to thyroid hormone ther-apy. The
following are previous notable and more recentexamples:
Basal metabolic rate was the gold standard for diag-nosis.
Extremely high and low values correlate well withmarked
hyperthyroidism and hypothyroidism, respec-tively, but are affected
by many unrelated, diverseconditions, such as fever, pregnancy,
cancer, acromeg-aly, hypogonadism, and starvation (97,98).
Decrease in sleeping heart rate (61) Elevated total cholesterol
(62,99) as well as low-densitylipoprotein (LDL) (99,100) and the
highly atherogenicsubfraction Lp (a) (101)
Delayed Achilles reflex time (60) Increased creatine kinase due
to an increase in the MMfraction, which can be marked and lead to
an increase inthe MB fraction. There is a less marked increase
inmyoglobin (66) and no change in troponin levels even inthe
presence of an increased MB fraction (102).
Screening and aggressive case findingfor hypothyroidism
Criteria for population screening include:
A condition that is prevalent and an important healthproblem
Early diagnosis is not usually made Diagnosis is simple and
accurate Treatment is cost effective and safe
Despite this seemingly straightforward guidance, expertpanels
have disagreed about TSH screening of the generalpopulation (Table
8). The ATA recommends screening in alladults beginning at age 35
years and every 5 years thereafter
Table 7. Thyrotropin Upper Normal
Group, study, society TSH upper normal Comments
NACB 2.5 When there is no evidence of thyroid diseaseNHANES III,
disease free 4.5 No self-reported thyroid disease
Not on thyroid medicationsNHANES III, reference population 4.12
No self-reported thyroid disease
Not on thyroid medicationsNegative anti-thyroid antibodiesNot
pregnantNot on estrogens, androgens, lithium
Hanford Thyroid Disease Study 4.10 No evidence of thyroid
diseaseNegative anti-thyroid antibodiesNot on thyroid
medicationsNormal ultrasound (no nodules or thyroiditis)
Pregnancy, first trimester 2.02.5 See sections L-thyroxine
treatment of hypothyroidismand Hypothyroidism during pregnancy
Pregnancy, second trimester 3.0 See sections L-thyroxine
treatment of hypothyroidismand Hypothyroidism during pregnancy
Pregnancy, third trimester 3.5 See sections L-thyroxine
treatment of hypothyroidismand Hypothyroidism during pregnancy
Sources: Stagnaro-Green et al., 2011 (10); Hollowell et al.,
2002 (11); Hamilton et al., 2008 (81); Baloch et al., 2003
(85).NACB, National Academy of Clinical Biochemists; NHANES,
National Health and Nutrition Examination Survey.
PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS 1209
-
(103). AACE recommends routine TSHmeasurement in
olderpatientsage not specifiedespecially women (2). TheAmerican
Academy of Family Physicians recommends rou-tine screening in
asymptomatic patients older than age 60years (104), and the
American College of Physicians recom-mends case finding in women
older than 50 years (105). Incontrast, a consensus panel (106), the
Royal College of Phy-sicians of London (107), and the U.S.
Preventive Services TaskForce (108) do not recommend routine
screening for thyroiddisease in adults. For recommendations in
pregnancy, seeRecommendations 20.1.1 and 20.1.2.
While there is no consensus about population screening
forhypothyroidism there is compelling evidence to support
casefinding for hypothyroidism in:
Those with autoimmune disease, such as type 1
diabetes(20,21)
Those with pernicious anemia (109,110) Those with a first-degree
relative with autoimmunethyroid disease (19)
Those with a history of neck radiation to the thyroidgland
including radioactive iodine therapy for hyper-thyroidism and
external beam radiotherapy for headand neck malignancies
(111113)
Those with a prior history of thyroid surgery or
dys-function
Those with an abnormal thyroid examination Those with
psychiatric disorders (114) Patients taking amiodarone (37) or
lithium (3234) Patients with ICD-9 diagnoses as presented in Table
9
When to treat hypothyroidism
Although there is general agreement that patients withprimary
hypothyroidism with TSH levels above 10mIU/L
should be treated (106,115117), which patients with TSHlevels of
4.510mIU/L will benefit is less certain (118,119). Asubstantial
number of studies have been done on patientswith TSH levels between
2.5 and 4.5, indicating beneficialresponse in atherosclerosis risk
factors such as atherogeniclipids (120123), impaired endothelial
function (124,125), andintimamedia thickness (126). This topic is
further discussed inthe section Cardiac benefit from treating
subclinical hypothyroid-ism. However, there are virtually no
clinical outcome data tosupport treating patients with subclinical
hypothyroidismwith TSH levels between 2.5 and 4.5mIU/L. The
possibleexception to this statement is pregnancy because the rate
ofpregnancy loss, including spontaneous miscarriage before 20weeks
gestation and stillbirth after 20 weeks, have been re-ported to be
increased in anti-thyroid antibodynegativewomen with TSH values
between 2.5 and 5.0 (127).
L-thyroxine treatment of hypothyroidism
Since the generation of biologically active T3 by the
pe-ripheral conversion of T4 to T3 was documented in 1970
(128),L-thyroxine monotherapy has become the mainstay of treat-ing
hypothyroidism, replacing desiccated thyroid and otherforms of
L-thyroxine and L-triiodothyronine combinationtherapy. Although a
similar quality of life (129) and circulat-ing T3 levels (130) have
been reported in patients treated withL-thyroxine compared with
individuals without thyroid dis-ease, other studies have not shown
levels of satisfactioncomparable to euthyroid controls (131). A
number of studies,following a 1999 report citing the benefit of
L-thyroxine and L-triiodothyronine combination therapy (132), have
re-ad-dressed the benefits of synthetic L-thyroxine and
L-triio-dothyronine combination therapy but have largely failed
toconfirm an advantage of this approach to improve cognitiveor mood
outcomes in hypothyroid individuals treatedwith L-thyroxine alone
(133,134).
Yet severalmatters remain uncertain.What should the ratiosof
L-thyroxine and L-triiodothyronine replacement be (133)?What is the
pharmacodynamic equivalence of L-thyroxine and
Table 9. ICD-9-CM Codes to SupportThyrotropin Testing
Adrenal insufficiency 255.41Alopecia 704.00Anemia, unspecified
deficiency 281.9Cardiac dysrhythmia, unspecified 427.9Changes in
skin texture 782.8Congestive heart failure 428.0Constipation
564.00Dementia 294.8BADiabetes mellitus, type 1 250.01Dysmenorrhea
625.3Hypercholesterolemia 272.0Hypertension 401.9Mixed
hyperlipidemia 272.2Malaise and fatigue 780.79Myopathy, unspecified
359.9Prolonged QT interval 794.31Vitiligo 709.01Weight gain
783.9M
ICD-9-CM, International Classification of Diseases, Ninth
Revi-sion, Clinical Modification
(www.cdc.gov/nchs/icd/icd9cm.htm).
Table 8. Recommendations of Six OrganizationsRegarding Screening
of Asymptomatic Adults
for Thyroid Dysfunction
Organization Screening recommendations
American ThyroidAssociation
Women and men > 35 yearsof age should be screenedevery 5
years.
American Associationof ClinicalEndocrinologists
Older patients,especially women,should be screened.
American Academyof Family Physicians
Patients 60 years of ageshould be screened.
American College ofPhysicians
Women 50 years of agewith an incidental findingsuggestive of
symptomaticthyroid disease should beevaluated.
U.S. Preventive ServicesTask Force
Insufficient evidence foror against screening
Royal Collegeof Physiciansof London
Screening of the healthyadult population unjustified
Sources: Baskin et al., 2002 (2); Ladenson et al., 2000 (103);
AmericanAcademy of Family Physicians, 2002 (104); Helfand and
Redfern,1998 (105); Vanderpump et al., 1996 (107); Helfand, 2004
(108).
1210 GARBER ET AL.
-
L-triiodothyronine (135)? It was previously believed to be
1:4,but a recent small study indicated that it was approximately
1:3(135). Why do some patients prefer combination therapy to
L-thyroxine monotherapy (133)? Some insight into the latterquestion
may be gained from a large-scale study of L-thyroxineand
L-triiodothyronine combination therapy in which differentresponses
were observed in patients with different genetic sub-types of type
2 deiodinase (136), despite a prior, smaller negativestudy (137).
It is not known if thosewho responded positively toL-thyroxine and
L-triiodothyronine combination therapy willhave long-term benefit
and whether genotyping patients withhypothyroidismwho are
clinically and biochemically euthyroidwill ultimately reliably
identify patients with hypothyroidismwho are most likely to benefit
from combination therapy.
Treatment of hypothyroidism is best accomplished usingsynthetic
L-thyroxine sodium preparations. Because of theuniqueness of the
various tablet formulations and a recentlyintroduced preparation of
liquid-containing capsules with theinactive ingredients gelatin,
glycerin, and water, and becauseof uncertainty about the
sensitivity of current bioequivalenceassessment procedures to
assure true interchangability amongthe tablets, current
recommendations encourage the use of aconsistent L-thyroxine
preparation for individual patients tominimize variability from
refill to refill (138,139).
Some reports have indicated an apparent increased
dosagerequirement for L-thyroxine in some patients with
diminishedgastric acid secretion (140,141). This has led to in
vitrowork showing significant differences in dissolution among
L-thyroxine preparations (142), profiles of which appear to
bedependent on the pH of the solution in which the preparationswere
dissolved. The liquicap preparation (Tirosint) (143) dis-solution
profile was the least affected by changes in pH (142).The clinical
significance of these findings remains unclear. Inmore recent,
though short-term studies, the use of histamineH2receptor blockers
and proton pump inhibitors does not appearto influence clinical
measures in L-thyroxine tablettreated pa-tients (144).
Desiccated thyroid has not been systematically studied
(seeDietary supplements and nutraceuticals in the treatment of
hypo-thyroidism). Absorption studies indicate that the
bioavailabilityof T3 in desiccated thyroid is comparable to that of
orally ad-ministered synthetic L-triiodothyronine (145). Therefore,
themost commonly used form of desiccated thyroid, known asArmour
Thyroid, which is of porcine origin, may be viewedas a L-thyroxine
and L-triiodothyronine combination with aratio of approximately 4:1
by weight (145). The content ofthyroid hormone and the ratio of T4
to T3 may vary in desic-cated thyroid preparations depending on the
brand employedand whether it is of porcine or bovine origin.
The daily dosage of L-thyroxine is dependent on age, sex,and
body size (146151). Ideal body weight is best used forclinical dose
calculations because lean body mass is the bestpredictor of daily
requirements (152,153). A recent study,however, which did not
subclassify patients on the basis oftheir initial degree of
hypothyroidism, found that while the L-thyroxine dose per ideal
body weight or degree of overweightdiffered by sexwith females
having a higher dose require-ment than menit did not confirm that
age was an indepen-dent predictor of dosage (154).
With little residual thyroid function, replacement
therapyrequires approximately 1.6 lg/kg of L-thyroxine
daily(155,156). Patients who are athyreotic (after total
thyroid-
ectomy and/or radioiodine therapy) (157) and those withcentral
hypothyroidism may require higher doses (158),while patients with
subclinical hypothyroidism (159162)or after treatment for Graves
disease (163) may require less.Young healthy adults may be started
on full replacementdosage, which is also preferred after planned
(in prepara-tion for thyroid cancer imaging and therapy) or
short-terminadvertent lapses in therapy. Starting with full
replace-ment versus low dosages leads to more rapid normalizationof
serum TSH but similar time to symptom resolution (164).However,
patients with subclinical hypothyroidism do notrequire full
replacement doses (159). Doses of 2575 lgdaily are usually
sufficient for achieving euthyroid levels(160), with larger doses
usually required for those pre-senting with higher TSH values
(161). One randomizedcontrol trial assigned L-thyroxine doses on
the basis of theinitial serum TSH values as follows: 25 lg for TSH
4.08.0mIU/L, 50 lg for TSH 812mIU/L, and 75 lg forTSH > 12mIU/L.
After 2 months only minimal further ad-justments were required to
achieve euthyroidism (162).
One recent study demonstrated that L-thyroxine absorptionwithin
30 minutes of breakfast is not as effective as when it istaken 4
hours after the last meal (165). Another study showedthat taking it
60minutes before breakfast on an empty stomachwas better than
taking it within 2 hours of the last meal of theday, which in turn
was better than taking it within 20 minutesof breakfast (166).
However, these two studies do not establishwhich of the two
methods, L-thyroxine taken with water 60minutes before breakfast or
at bedtime 4 hours after the lastmeal on an empty stomach, is
superior. Although L-thyroxineis better absorbed when taken 60
minutes before a mealcompared to 30 minutes before a meal,
compliance may beenhanced by instructing patients to consistently
take it withwater between 30 and 60 minutes prior to eating
breakfast.
L-thyroxine should be stored per product insert at 20C25C,
(range, 15C30C) or 68F77F (range, 59F86F) andprotected from light
andmoisture. It should not be takenwithsubstances or medications
(see Table 10) that interfere with itsabsorption or metabolism.
Because approximately 70% of anorally administered dose of
L-thyroxine is absorbed (167169), individuals unable to ingest
L-thyroxine should initiallyreceive 70% or less of their usual dose
intravenously. CrushedL-thyroxine suspended in water should be
given to patientsreceiving enteral feeding through nasogastric and
other tubes.For optimal absorption feeding should be interrupted
withdoses given as long as possible after feeding and at least
1hour before resuming feeding. Administering intravenous
L-thyroxine solution, which is not universally available, shouldbe
considered when feeding may not be interrupted.
Dose adjustments are guided by serum TSH determinations48 weeks
(156,170) following initiation of therapy, dosageadjustments, or
change in the L-thyroxine preparation(139,171). While TSH levels
may decline within a month ofinitiating therapywith doses of
L-thyroxine such as 50 or 75lg,making adjustments with smaller
doses may require 8 weeksor longer before TSH levels begin to
plateau (170,172). Incre-ment changes of 12.525lg/d are initially
made, but evensmaller changes may be necessary to achieve goal TSH
levels.
In the case of central hypothyroidism, estimates of dosagebased
on 1.6lg/kg L-thyroxine daily and assessment of free T4,not TSH,
should guide therapy. Determinations are bestdone prior to taking
thyroid hormone. The goal of therapy is
PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS 1211
-
Table 10. Agents and Conditions Having an Impact on L-thyroxine
Therapyand Interpretation of Thyroid Tests
10.1. Interference with absorption
Bile acid sequestrants (cholestyramine,colestipol,
colesevelam)
SucralfateCation exchange resins (Kayexelate)Oral
bisphosphonatesProton pump inhibitorsRaloxifenea
Multivitamins (containing ferroussulfate or calcium
carbonate)
Ferrous sulfatePhosphate binders (sevelamer,aluminum
hydroxide)
Calcium salts (carbonate, citrate, acetate)Chromium
picolinateCharcoalOrlistatb
CiprofloxacinH2 receptor antagonistsa
Malabsorption syndromes Celiac disease Jejunoileal bypass
surgery Cirrhosis (biliary) Achlorhydria
Diet Ingestion with a meal Grapefruit juicea Espresso coffee
High fiber diet Soybean formula (infants) Soy
10.2. Thyroid gland hormone production and secretion
Direct and indirect effectson the thyroid gland Iodine uptake+
Iodine (including kelp
supplements)+ Amiodarone+ Ethionamide+ Iodinated contrast
(ipodate,c iopanoic acidc)+ Perchloratec
Hormone production+ Iodine (including kelp
supplements)+ Amiodarone+ Thionamides (carbimazole,
methimazole, propylthiouracil)+ Iodinated contrast
(ipodate,c iopanoic acidc)
+ Sulfonylureas+ Sulfonamides+ Ethionamide
Secretion+ Lithium+ Iodine (including kelp
supplements)+ Amiodarone+ Iodinated contrast
(ipodate,c iopanoic acidc) Thyroiditis+ Induces- Amiodarone-
Tyrosine kinase inhibitors(sunitinib, sorafenib)
- Interferon alpha- Interleukins
- Antiangiogenic(lenalidomide, thalidomide)
- Lithium- Alemtuzumab- Denileukin diftitoxin
+ Ameliorates (if autoimmune)- Glucocorticoids
Development of Graves+ Interferon alpha+ HAART (highly
activeantiretroviral therapy)
+ Alemtuzumab Amelioration of Graves+ Glucocorticoids
10.3. Direct and indirect effects on the
hypothalamicpituitarythyroid axis
TSH secretion Decrease+ Bexarotene+ Dopamine+ Dopaminergic
agonists(bromocriptine, cabergoline)
+ Glucorticoids+ Thyroid hormone analogues
+ Somatostatin analogues(octreotide, lanreotide)
+ Metformin+ Opiates (e.g., heroin)+ Interleukin-6
Increase+ Dopamine receptor
blockers (metoclopramide)
+ Hypoadrenalism+ Interleukin 2+ Amphetamine+ Ritonavirb
+ St. Johns Worta
Hypophysitis Ipilimumab
10.4. Increased clearance 10.5. Peripheral metabolism
PhenobarbitalPrimidonePhenytoinCarbamazepineOxacarbazepineb
RifampinGrowth hormone
Sertralineb
Tyrosine kinase inhibitors(imatinib,b sunitinib)
Quetiapineb
Stavudineb
Nevirapinea,b
GlucocorticoidsAmiodaronePropylthiouracilBeta blockers (e.g.,
propranolol,nadolol)
Iodinated contrast (ipodate,c
iopanoic acidc)Interleukin-6Clomipramine
aImpact uncertain.bMechanism uncertain.cNot presently available
in the United States.
1212 GARBER ET AL.
-
generally to attain values above the mean for assays
beingemployed, in keeping with observations that mean values
forestimates of free T4 in patients who are treatedwith
L-thyroxinetend to be higher than mean values observed in
untreatedcontrols (150,173175).
Some clinical manifestations of hypothyroidism, such aschronic
skin changes, may take up to 36 months to resolveafter serum TSH
has returned to normal (176).
Once an adequate replacement dosage has been deter-mined most,
but not all of us, are of the opinion that periodicfollow-up
evaluationswith repeat TSH testing at 6-month andthen 12-month
intervals are appropriate (172). Some authorsthink that more
frequent testing is advisable to ensure andmonitor compliance with
therapy.
Dosage adjustments may be necessary as underlyingfunction wanes.
In pregnancy thyroid hormone require-ments are increased, then
revert back to baseline after de-livery (177). Dosage adjustments
are also necessary,generally when medications influencing
absorption, plasmabinding, or metabolism are added or discontinued.
Whensuch medications are introduced or discontinued thyroidhormone
levels should initially be checked within 48 weeksof doing so, and
tests performed at least every 48 weeksuntil stable euthyroid
indices have been documented whileon the same dose of L-thyroxine.
Decreases in L-thyroxinerequirements occur as patients age (151)
and following sig-nificant weight loss. Moreover, although elderly
patientsabsorb L-thyroxine less efficiently they often require
20-25% less per kilogram daily than younger patients, due
todecreased lean bodymass (152,153). Regardless of the degreeof
hypothyroidism, patients older than 5060 years, withoutevidence of
coronary heart disease (CHD) may be started ondoses of 50 lg daily.
Among those with known CHD, theusual starting dose is reduced to
12.525 lg/day. Clinicalmonitoring for the onset of anginal symptoms
is essential(178). Anginal symptoms may limit the attainment of
eu-thyroidism. However, optimal medical management of
ar-teriosclerotic cardiovascular disease (ASCVD) shouldgenerally
allow for sufficient treatment with L-thyroxine toboth reduce the
serum TSH andmaintain the patient angina-free. Emergency coronary
artery bypass grafting in patientswith unstable angina or left main
coronary artery occlusionmay be safely performed while the patient
is still moderatelyto severely hypothyroid (179,180) but elective
cases shouldbe performed after the patient has become
euthyroid.
The exacerbation of adrenal insufficiency was first de-scribed
in cases of central hypothyroidism over 70 years ago(181). Although
it rarely occurs, those with adrenal insuffi-ciency, either primary
or central, or at risk for it, should betreated with clinically
appropriate doses of hydrocortisoneuntil adrenal insufficiency is
ruled out (182,183). In the ab-sence of central hypothyroidism,
elevated TSH levels may beseen in conjunction with normal T4
levels, making it initiallyindistinguishable from subclinical
hypothyroidism. How-ever, when due to adrenal insufficiency
elevated TSH levelsfall with glucorticoid therapy alone
(54,55).
Patients on high doses of L-thyroxine ( > 200 lg/d)
withpersistently or frequently elevated TSH levels may be
non-compliant or have problems with L-thyroxine absorption(171).
The former is much more common (184). Althoughdaily dosing of
L-thyroxine is ideal, missed doses should bemade up when the
omission is recognized, even on the same
or subsequent days. In those with significant
complianceproblems, weekly dosing with L-thyroxine results in
similarclinical safety, outcomes, and acceptable TSH values
(185).Absorption is diminished by meals (165,166,168,186)
andcompeting medications (see Table 10).
Steps should be taken to avoid overtreatment with L-thyroxine.
This has been reported in 20% of those treated withthyroid hormone
(12). The principal adverse consequences ofsubtle or frank
overtreatment are cardiovascular (187190),skeletal (191194), and
possibly affective disturbances (195197). The elderly are
particularly susceptible to atrial fibrillation,while
postmenopausal women, who constitute a substantialportion of those
on thyroid hormone, are prone to acceleratedbone loss.
Therapeutic endpoints in the treatmentof hypothyroidism
The most reliable therapeutic endpoint for the treatment
ofprimary hypothyroidism is the serum TSH value. Con-firmatory
total T4, free T4, and T3 levels do not have sufficientspecificity
to serve as therapeutic endpoints by themselves,nor do clinical
criteria. Moreover, when serum TSH is withinthe normal range, free
T4 will also be in the normal range. Onthe other hand, T3 levels
may be in the lower reference rangeand occasionally mildly
subnormal (150).
The normal range for TSH values, with an upper limit of4.12mIU/L
is largely based on NHANES III (11) data, but ithas not been
universally accepted. Some have proposed thatthe upper normal
should be either 2.5 or 3.0mIU/L (86) for anumber of reasons:
The distribution of TSH values used to establish thenormal
reference range is skewed to the right by valuesbetween 3.1 and
4.12mIU/L.
The mean and median values of approximately1.5mIU/L are much
closer to the lower limit of the re-ported normal reference range
than the upper limit.
When risk factors for thyroid disease are excluded, theupper
reference limit is somewhat lower.
The counter arguments are that while many with TSH valuesbetween
2.53.0 and 4.12mIU/L may have early hypothy-roidism, many do not.
Data to support treating patients in thisrange are lacking, with
the exception of data in pregnancy (seeConcurrent conditions of
special significance in hypothyroidpatientsHypothyroidism during
pregnancy). Though pa-tients without thyroid disease have stable
mean TSH values,measurements vary up to 50% above (78) and below
themeanon a given day. Thus, if the upper normal of TSH were
con-sidered to be 2.5mIU/L, patients withmean values just abovethe
mean NHANES III value of 1.5mIU/L would frequentlybe classified as
hypothyroid when they are not (78,87). Thiswould lead to more than
10 million additional diagnoses ofhypothyroidism in the United
States per yearwithout clear-cut benefit. The controversy has not
only contributed to thedebate about what TSH values should prompt
treatment, butalso what the target TSH should be for patients being
treatedfor hypothyroidism. Data concerning clinical benefit
arelacking to support targeting to reach low normal or subnor-mal
TSH levels in the treatment of hypothyroidism (198,199).As a
result, in patients who are not pregnant, the target rangeshould
bewithin the normal range. If upper and lower normal
PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS 1213
-
values for a third generation TSH assay are not available,
therange used should be based on the NHANES III referencepopulation
range of 0.454.12. Although there are substantialnormative data
establishing what trimester specific normalranges are for pregnancy
(200207) (see Table 7, TSH upperrange of normal), there are no
prospective trials establishingoptimal target TSH ranges for
patients with hypothyroidismwho are pregnant and are being treated
with L-thyroxine. Thelower range of normal for serum TSH in
pregnancy is gen-erally 0.10.2mIU/L lower than the normal range for
thosewho are not pregnant (10).
The appropriate target TSH values treatment for treatingpatients
with differentiated thyroid cancer, goiter, and nod-ular thyroid
disease are beyond the scope of these guidelines.
When to consult an endocrinologist
Although most physicians can diagnose and treat hypo-thyroidism,
consultation with an endocrinologist is re-commended in the
following situations:
Children and infants Patients in whom it is difficult to render
and maintain aeuthyroid state
Pregnancy Women planning conception Cardiac disease Presence of
goiter, nodule, or other structural changes inthe thyroid gland
Presence of other endocrine disease such as adrenal andpituitary
disorders
Unusual constellation of thyroid function test results Unusual
causes of hypothyroidism such as those in-duced by agents listed in
Table 10.
The basis for these recommendations stems from observa-tions
that cost-effective diagnostic evaluations and improvedoutcomes in
the medical and surgical evaluation and man-agement of thyroid
disorders such as nodular thyroid diseaseand thyroid cancer are
positively correlatedwith the volume ofexperience a surgeon has or
whether or not the patient wasevaluated by an endocrinologist
(208210). In addition, endo-crinologists were more knowledgeable
about thyroid diseaseand pregnancy than obstetrician-gynecologists,
internists, andfamily physicians (211). Observational studies
comparing careprovided by endocrinologists with nonendocrinologists
forcongenital, pediatric, and central hypothyroidism as well
theuncommon, challenging clinical situations just listed, whichare
regularly addressed by clinical endocrinologists, are lack-ing, and
controlled studies would be unethical.
Concurrent conditions of special significancein hypothyroid
patients
Hypothyroidism during pregnancy. Overt untreated hy-pothyroidism
during pregnancy may adversely affect maternaland fetal outcomes.
These adverse outcomes include increasedincidences of spontaneous
miscarriage, preterm delivery, pre-eclampsia,maternal hypertension,
postpartumhemorrhage, lowbirth weight and stillbirth, and impaired
intellectual and psy-chomotor development of the fetus (212214).
While there isevidence to suggest that subclinical hypothyroidism
in earlypregnancymay also be associatedwith impaired intellectual
andpsychomotor development (215218), and that this impairment
may be prevented with L-thyroxine treatment (217,218), this
isnot supported by a recent randomized control trial (219).
Finally,womenwith positive TPOAbmayhave an increased risk for
firsttrimester miscarriage (220), preterm delivery (221), and for
off-spring with impaired cognitive development (218,222). This
riskmay be due to reduced thyroid functional reserve from
chronicautoimmune thyroiditis leading to subtle hypothyroidism
(223).One European study has shown that treatment with
L-thyroxinereduced the risk of miscarriage to that of
TPOAb-negativeeuthyroid controls (224). A recent prospective study
done inChina showed that intellectual and psychomotor developmentof
offspring born to women with positive TPOAb and normalthyroid
function who were treated with L-thyroxine by 8 weeksof gestation
had intellectual and psychomotor developmentcomparable to controls
(218). Finally, treatmentwith L-thyroxinebefore conception has been
shown to reduce themiscarriage rateand to increase live birth rate
in women with subclinical hypo-thyroidism undergoing assisted
reproduction (225).
A sustained rise in serum total T4 and a drop in serum
TSHcharacterize the early stage of normal pregnancy. Studies
offetal development and at least one outcome study done inEurope
suggest that early central nervous system develop-ment requires
adequate transplacental T4 transport (226231).The offspring of
mothers with serum T4 levels in the lowest10th percentile of the
reference range at the end of the firsttrimester have been reported
to have subnormal intellectualdevelopment even if TSH levels are
normal (228231). Basedon these findings, desiccated thyroid and
L-thyroxine/L-triiodothyronine combinations, which cause lowering
ofserum T4 levels, should not be used during pregnancy.
Fur-thermore, patients being treated with these preparationsshould
be switched to L-thyroxine when planning to conceiveand at the very
latest when found to be pregnant. At this timeTSH should also be
measured. A more recent study done inGreater Boston, which is
iodine sufficient, however, did notdemonstrate a relationship
between fetal intellectual devel-opment and maternal serum T4
levels (232).
When a woman with hypothyroidism becomes pregnant,the dosage of
L-thyroxine should be increased as soon aspossible to ensure that
serum TSH is < 2.5mIU/L and thatserum total T4 is in the normal
reference range for pregnancy.Moreover, when a patient with a
positive TPOAb test be-comes pregnant, serum TSH should be measured
as soon aspossible and if it is >2.5mIU/L, L-thyroxine treatment
shouldbe initiated. Serum TSH and total T4 measurements should
bemonitored every 4 weeks during the first half of pregnancy(233)
and at least once between 26 and 32 weeks gestation toensure that
the requirement for L-thyroxine has not changed.Some of us would
continue to monitor thyroid indices after 32weeks in order to
confirm that thyroid indices are in thenormal range. L-thyroxine
dosages should be adjusted as in-dicated, aiming for TSH levels
that are within the normalrange for that phase of pregnancy
(177,200207,234238).Some advocate doing so more frequently in order
to ensurecompliance and the efficacy of dose adjustments, as
reflectedby dropping TSH levels. Total T4 increases predictably
duringpregnancy and, as already noted, the reference range
is*1.5fold that of the nonpregnant range. Serum TSH levels
declinein the first trimester when serum human chorionic
gonado-tropin levels are high and rise after 1012 weeks
gestation.While the upper limit of normal for the first trimester
is gen-erally < 2.5mIU/L respective upper normal values for
the
1214 GARBER ET AL.
-
second and third trimesters are approximately 3.0
and3.5mIU/L.
Diabetes mellitus. Approximately 10% of patients withtype 1
diabetes mellitus will develop chronic thyroiditis (53)during their
lifetime, which may lead to the insidious onset ofsubclinical
hypothyroidism. Patients with diabetes should beexamined for the
presence and development of a goiter.Sensitive TSH measurements
should be obtained at regularintervals in patients with type 1
diabetes, especially if a goiterdevelops or if evidence is found of
other autoimmune disor-ders. In addition, postpartum thyroiditis
will develop in up to25% of women with type 1 diabetes (239).
Infertility. Some patients with infertility and
menstrualirregularities have underlying chronic thyroiditis in
conjunc-tion with subclinical or overt hypothyroidism.
Moreover,TPOAb-positive patients, even when euthyroid, have an
ex-cess miscarriage rate (220,224). Typically, these patients
seekmedical attention because of infertility or a previous
miscar-riage, rather than hypothyroidism.
A careful, comprehensive history, physical examination,and
appropriate laboratory evaluation can identify chronicthyroiditis.
It has long been recognized that in some withpatients with overt
hypothyroidism, thyroid hormone re-placement therapy may normalize
the menstrual cycle andrestore normal fertility (6365).
Obesity. Hypothyroidism and obesity are often linked atleast in
the consciousness of the lay public. However, appetitein those with
marked hypothyroidism is often suppressedoffsetting the impact of a
decrease in metabolic rate, myx-edema may present with weight loss,
and overt hypothy-roidism does not appear to be more common in the
obesepopulation than in the general population (240).
Nonethelessthis impression dates back to early observations of
significantweight loss following the resolution of myxedema, an
effectthat was principally the result of fluid mobilization (241).
Thiswas recently confirmed in a prospective year-long study ofnewly
diagnosed patients with overt hypothyroidism whosemean TSH levels
at the onset of the study was 102 (242). Someobservational studies
correlate TSH levels with body mass in-dex (243245) while others do
not (246). However, obesity mayhave an impact on the
hypothalamicpituitarythyroid axis asevidenced by relatively
elevated TSH levels in morbidly obeseadults (247) and children
(248) who have ultrasound findingssuggestive of chronic thyroiditis
without either elevated anti-thyroid antibody titers or decreased
T4 and T3 levels. Cautionmust therefore be exercised when
diagnosing subclinical hy-pothyroidism in the setting of marked
obesity (249).
Apart from the mobilization of fluid and the ensuing di-uresis
in myxedematous states, however, the impact ofthyroid hormone
therapy on waisthip ratio (250) andweight loss (242), even in cases
of profound hypothyroidism,appears at most to be modest. This is
despite the fact thatresting energy expenditure increases
significantly in indi-viduals who are rendered subclinically
hyperthyroid afterbeing subclinically hypothyroid (251). Clearly
behavioraland other physiological factors apart from thyroid
statushave an impact on weight status. Because of the
negativeimpact on nitrogen balance, cardiovascular factors,
bone,and affective status, supraphysiological doses of thyroid
hormone as used in the past (252,253) should not be em-ployed as
an adjunct to weight loss programs in patientswith or without
hypothyroidism (254). However, it is ad-visable to counsel patients
about the effect any change inthyroid status may have on weight
control. This includesthyroidectomy although recent studies
concerning its effectare contradictory (255,256).
Patients with normal thyroid tests. Patients with symp-toms of
hypothyroidism, but normal thyroid hormone levelsdo not benefit
from treatment with L-thyroxine (257). More-over, treatment confers
a substantial risk of subclinical orovert hyperthyroidism, which in
one large-scale study wasapproximately 20% (12).
Depression. The diagnosis of subclinical or overt
hypo-thyroidism must be considered in every patient with
depres-sion. In fact, a small proportion of all patients with
depressionhave primary hypothyroidismeither overt or
subclinical.Those with autoimmune disease are more likely to have
de-pression (258) as are those with postpartum thyroiditis
re-gardless of whether the hypothyroidism is treated or not
(259).
All patients receiving lithium therapy require periodicthyroid
evaluation because lithium may induce goiter andhypothyroidism
(3234). Occasionally in psychiatric practice,some patients who have
depression are treated not only withantidepressants but also with
thyroid hormone, even thoughthey have normal thyroid function. No
firm evidence hasshown that thyroid hormone treatment alone does
anythingto alleviate depression in such patients.
Substantial evidence supports the use of thyroid hormoneto treat
the mood disturbances associated with hypothy-roidism (114).
Interesting animal data link the use of bothtricyclic
antidepressants (TCAs) and selective serotonin re-uptake inhibitors
(SSRIs) to potential changes in brain thy-roid hormone metabolism,
which make the combination ofL-triiodothyronine with these an
appealing therapeutic hy-pothesis (114). However, the clinical data
from randomizedcontrolled trials evaluating the acceleration and
augmentationof response with TCA as well as
SSRI/L-triiodothyroninecombinations are inconsistent (114,260,261)
and do not clearlysupport L-triiodothyronine use in euthyroid
depressed subjects.
Nonthyroidal illness. The evaluation of thyroid functionin
chronically or markedly acutely ill patients may be con-fusing.
Medications, such as glucocorticoids (90), amiodarone(37), and
dopamine (89) may have an impact on thyroidhormone levels and in
the case of amiodarone, amarked effecton thyroid status. In
addition, major illness and starvationmay be accompanied by a
change in thyroid hormone econ-omy, resulting in a low serum T3 and
normal or low serum T4and TSH levels (262,263). Since there is
evidence that treat-ment with either L-thyroxine (264) or
L-triiodothyronine (265)is of no benefit, patients who are not
clearly hypothyroidshould not be treated until their acute medical
condition hasresolved. A 2010 study showed that infants under
5months ofage undergoing cardiac surgery for complex congenital
heartdisease benefited from intravenous L-triiodothyronine
treat-ment (266), raising the possibility that under certain
circum-stances treating nonthyroidal illness with thyroid
hormonemay be beneficial. In addition, patients withNYHA class III
orIV heart failure with low serum T3 levels have been shown to
PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS 1215
-
benefit from intravenous L-triiodothyronine to restore serumT3
levels to normal (267). Evaluation of the patient by a
clinicalendocrinologist is appropriate before initiation of
thyroidhormone treatment.
Dietary supplements and nutraceuticalsin the treatment of
hypothyroidism
The majority of dietary supplements (DS) fail to meet alevel of
scientific substantiation deemed necessary for thetreatment of
disease (268,269). In the case of hypothyroid-ism, this is the case
for over-the-counter products marketedfor thyroid support or as a
thyroid supplement orto promote thyroid health, among others. The
authorsdo not recommend the use of these or any unproven ther-apies
(269).
DS are generally thought of as various vitamins, minerals,and
other natural substances, such as proteins, herbs, andbotanicals.
The U.S. Food and Drug Administration (FDA)1994 Dietary Supplement
Health and Education Actexpanded the definition of DS as follows
(270):
DSHEA 1994 x3(a). (ff) The term dietary supplement:(1) means a
product (other than tobacco) that is intended
to supplement the diet that bears or contains one ormore of the
following dietary ingredients: a vitamin, amineral, an herb or
other botanical, an amino acid, adietary substance for use by man
to supplement thediet by increasing the total dietary intake, or a
con-centrate, metabolite, constituent, extract, or combina-tion of
any [of these ingredients].
(2) means a product that is intended for ingestion in
[pill,capsule, tablet, or liquid form]; is not represented foruse
as a conventional food or as the sole item of a mealor diet; and is
labeled as a dietary supplement.
(3) [paraphrased] includes products such as an approvednew drug,
certified antibiotic, or licensed biologic thatwas marketed as a
dietary supplement or food beforeapproval, certification, or
license (unless the Secretaryof Health and Human Services waives
this provision).
Nutraceuticals (N), a term coined to reflect its nutritionorigin
and pharmaceutical action, do not have a regulatorydefinition. They
are dietary supplements that contain a con-centrated form of a
presumed bioactive substance originallyderived from a food, but
nowpresent in a non-foodmatrix, andused to enhance health in
dosages exceeding those obtainablefrom normal foods (268).
Guidelines for the use of DS/N inendocrinology have been previously
published byAACE (269) .Functional foods are those foods containing
substances havingphysiological actions beyond their simple
nutritional value.
Overlap of symptoms in euthyroidand hypothyroid persons
The symptoms of hypothyroidism are nonspecific andmimic symptoms
that can be associated with variations inlifestyle, in the absence
of disease, or those of many otherconditions. This is well
illustrated in the Colorado thyroiddisease prevalence study (12).
That study found that four ormore symptoms of hypothyroidism were
present in approx-imately 25% of thosewith overt hypothyroidism,
20% of those
with subclinical hypothyroidism, and in 17% of
euthyroidpatients. Although the differences were statistically
signifi-cant since 88% of the population studied was euthyroid,
9%had subclinical hypothyroidism, and only 0.4% were
overtlyhypothyroid, it is clear that there are many more
euthyroidpatients with symptoms suggestive of hypothyroidism
thanthose who are subclinica