Treatment of Primary Hypothyroidism in Adults - UpToDate

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Tratamiento del hipotiroidismo primario en adultos

Autor: Douglas S Ross, MD
Editor de sección: David S Cooper, MD
Editor adjunto: Jean E Mulder, MD
Todos los temas se actualizan a medida que se dispone de nueva evidencia y se completa nuestro proceso de revisión por pares .
Revisión de la literatura vigente hasta: junio de 2021. | Última actualización de este tema: 20 de mayo de 2021.
INTRODUCCIÓN
En la mayoría de los pacientes, el hipotiroidismo es una afección permanente que requiere tratamiento de
por vida. La terapia consiste en el reemplazo de la hormona tiroidea, a menos que el hipotiroidismo sea
transitorio (como después de una tiroiditis indolora o tiroiditis subaguda) o reversible (debido a un
fármaco que puede suspenderse). (Ver "Trastornos que causan hipotiroidismo" ).
El objetivo de la terapia es restaurar el estado eutiroideo, que se puede lograr fácilmente en casi todos los
pacientes mediante la administración oral de tiroxina sintética (T4, levotiroxina ). El tratamiento adecuado
revierte todas las manifestaciones clínicas del hipotiroidismo.
Este tema revisará los principales problemas que deben abordarse en el tratamiento de adultos con
hipotiroidismo primario manifiesto. El tratamiento del hipotiroidismo subclínico y central, así como el
hipotiroidismo en niños (congénito o adquirido), se discute por separado.
● (Ver "Hipotiroidismo subclínico en adultos no embarazadas" ).

● (Ver "Hipotiroidismo central" ).
● (Consulte "Tratamiento y pronóstico del hipotiroidismo congénito" ).
● (Consulte "Hipotiroidismo adquirido en la infancia y la adolescencia" ).
ENFOQUE DEL TRATAMIENTO
Nuestro enfoque, que se describe a continuación, concuerda en gran medida con las Directrices para el
tratamiento del hipotiroidismo de la American Thyroid Association (ATA) [ 1 ].
Definición de hipotiroidismo
● El hipotiroidismo primario manifiesto se caracteriza bioquímicamente por una concentración sérica

alta de hormona estimulante de la tiroides (TSH) y una concentración sérica baja de tiroxina libre (T4).
Las manifestaciones clínicas son muy variables, según la edad de inicio y la duración y gravedad de la
https://www.uptodate.com/contents/treatment-of-primary-hypothyroidism-in-adults/print?search=hipotiroidismo&source=search_result&selectedTitle=… 1/25
deficiencia de hormona tiroidea. (Consulte "Manifestaciones clínicas del hipotiroidismo" y "Diagnóstico

y detección del hipotiroidismo en adultas no embarazadas" ).
● El hipotiroidismo subclínico se caracteriza bioquímicamente por una alta concentración sérica de TSH
y una concentración sérica normal de T4 libre. La mayoría de los pacientes están asintomáticos. El
diagnóstico y el tratamiento del hipotiroidismo subclínico se revisan por separado. (Ver
"Hipotiroidismo subclínico en adultos no embarazadas" ).
● Central hypothyroidism caused by hypothalamic or pituitary disease is characterized by a low serum

T4 concentration and a serum TSH concentration that is not appropriately elevated. TSH may be low,
normal, or even slightly elevated (up to approximately 10 mU/L). The clinical manifestations of central
hypothyroidism are similar to but sometimes milder than those of primary hypothyroidism. The
diagnosis and management of central hypothyroidism are reviewed separately. (See "Central
hypothyroidism".)
All patients with overt primary (or central) hypothyroidism require treatment (regardless of symptoms),
unless the hypothyroidism is transient (as after painless thyroiditis or subacute thyroiditis) or reversible
(due to a drug that can be discontinued). (See "Disorders that cause hypothyroidism", section on 'Transient
hypothyroidism'.)
Thyroid hormone should not be prescribed to biochemically euthyroid individuals with nonspecific
symptoms (eg, fatigue, weight gain, depression). Thyroid hormone has been administered to euthyroid
patients with several clinical problems in whom it was hoped that outcome would be improved. These
include T3 therapy in patients undergoing coronary artery bypass graft surgery [2] and in those with
refractory depression in an attempt to enhance the response to antidepressant drug therapy. A meta-
analysis on the efficacy of thyroid hormone therapy in depressed patients was equivocal [3]. Although
there was evidence for overall benefit, the analysis limited to randomized, double-blind trials revealed no
benefit of synthetic T3. In addition, T3 did not help in an open-label study of patients with severe
depression [4]. Finally, T4 therapy in euthyroid patients with "hypothyroid symptoms" was no more
effective than placebo in ameliorating symptoms [5].
Goals of therapy — The goals of therapy are:
● Amelioration of symptoms
● Normalization of serum TSH secretion
● Reduction in the size of goiter (if present)
● Avoidance of overtreatment (iatrogenic thyrotoxicosis)
We aim to keep serum TSH within the normal reference range (approximately 0.5 to 5.0 mU/L). However, it
is important to note that there is an age-related shift towards higher TSH concentrations in older patients,
with an upper limit of normal of approximately 7.5 mU/L in 80 year olds. Among patients with goiter,
approximately 50 percent will have some decrease in goiter size, which lags behind the fall in TSH
secretion [6,7].
There is considerable controversy as to the appropriate upper limit of normal for serum TSH [8]. Most
laboratories have used values of approximately 4.5 to 5.0 mU/L. However, others have argued that the
upper limit of normal of the euthyroid reference range should be reduced to 2.5 mU/L because 95 percent
of rigorously screened, young, euthyroid volunteers have serum values between 0.4 and 2.5 mU/L [9]. In
contrast, others have reported that age-adjusted upper limits of normal for TSH should be higher than 4.5
to 5 mU/L, especially for patients over age 70 [10]. Until there are data demonstrating an adverse biologic
impact for serum TSH values between 2.5 and 5.0 mU/L, the wisdom of labeling such patients as
hypothyroid is questionable [11]. This topic is reviewed in detail separately. (See "Laboratory assessment of
thyroid function", section on 'Serum TSH'.)
The approach to patients with persistent symptoms of hypothyroidism despite a normal serum TSH level is
reviewed below. (See 'Persistent symptoms' below.)
STANDARD REPLACEMENT THERAPY
The treatment of choice for correction of hypothyroidism is synthetic thyroxine (T4, levothyroxine). T4 is a
prohormone with very little intrinsic activity. It is deiodinated in peripheral tissues to form T3, the active
thyroid hormone. This deiodination process accounts for approximately 80 percent of the total daily
production of T3 in normal subjects. Approximately 70 to 80 percent of a dose of T4 is absorbed and,
because the plasma half-life of T4 is long (seven days), once-daily treatment results in nearly constant
serum T4 and triiodothyronine (T3) concentrations when a steady state is reached [12].
T4 formulations — T4 is available in tablet, soft gel, and liquid formulations. Either a generic or a brand-
name formulation of T4 is acceptable. The brand-name and most generic formulations are available in
color-coded tablets at small increments in hormone content to allow precise titration of the dose according
to the serum concentration of TSH.
● Tablet versus soft gel capsule or liquid – Most patients are treated with a T4 tablet. While in one
study, the pharmacokinetics of the soft gel capsule were similar to tablets in healthy individuals [13], in
other studies, the soft gel capsule was less dependent upon gastric pH than a branded tablet [14,15].
Thus, the soft gel capsule or liquid is an option for patients with suspected poor absorption of the
standard solid tablet, especially in the presence of atrophic gastritis. It may also be better absorbed
after bariatric surgery [16]. However, another, less costly option is to increase the dose of a generic T4
tablet with monitoring of TSH.
● Generic versus brand name – Either a generic or a brand-name formulation of T4 is acceptable [17].
If a switch from one manufacturer to another is made by the pharmacy and the patient is concerned
regarding equivalent efficacy of the preparations, we measure a serum TSH six weeks after changing
preparations to document that the serum TSH is still within the therapeutic target. In a study from the
Netherlands during an unexpected shortage of one branded levothyroxine product, a higher
percentage of patients who switched brands had abnormal TSH levels, especially if their dose
exceeded 100 mcg/day [18].
There has been considerable controversy about the bioequivalence of the various T4 formulations. In
the past, variation in the T4 content of brand-name and generic formulations led many experts to
prefer a specific preparation [19]. In 1997, a study of two brand-name and two generic formulations of
T4, using US Food and Drug Administration (FDA)-recommended methodology for determining
bioequivalence, reported that all four preparations were equivalent [20]. The methodology used to
determine bioequivalence in the study is considered by some to be flawed since endogenous T4
concentrations were not taken into account [21].
Although the use of brand-name T4 products might be preferred theoretically to avoid the issue of
variable bioavailabilities when there is interchange of different generic preparations by the pharmacy,
often this is not possible, because of cost considerations. In addition, it has yet to be shown that
switching among various generic manufacturers is a clinical problem. In the United States, the
manufacturer of the generic preparation is included on the label.
Dose and monitoring
Initial dose — The average full replacement dose of T4 in adults is approximately 1.6 mcg/kg body
weight per day (112 mcg/day in a 70-kg adult), but the range of required doses is wide, varying from 50 to
≥200 mcg/day. T4 requirements correlate better with lean body mass than total body weight [22]. In one
study, the average full replacement dose after thyroidectomy was 1.76 mcg/kg body weight for body mass
index (BMI) <25 kg/m2, 1.47 mcg/kg for BMI 25 to 29 kg/m2, 1.42 mcg/kg for BMI 30 to 34 kg/m2, 1.27
mcg/kg for BMI 35 to 39 kg/m2, and 1.28 mcg/kg for BMI over 40 kg/m2 [23].
The initial dose can be the full anticipated dose (approximately 1.6 mcg/kg/day) in young, healthy patients
( algorithm 1). Older patients or those with coronary heart disease, in whom the duration of
hypothyroidism is unknown, should be started on a lower dose (25 to 50 mcg daily). If the duration of
hypothyroidism is known to be short, eg, less than approximately two months, starting doses in older
patients or in those with coronary heart disease can be two-thirds to three-quarters of the anticipated
dose needed to achieve a euthyroid state. (See 'Older patients or those with coronary heart disease'
below.)
In one prospective study of different starting doses of T4, 50 hypothyroid patients (mean age 47 years but
some patients were in their 70s and 80s) were randomly assigned to receive a full starting dose of T4 (1.6
mcg/kg/day) or T4 25 mcg/day with dose adjustments every four weeks. Euthyroidism was achieved more
rapidly in the full-dose group, but signs and symptoms of hypothyroidism and quality of life improved at a
similar rate in the two groups. No adverse cardiac effects were seen in either group, but the subjects in the
study, including the older patients, had been carefully screened to rule out cardiovascular disease prior to
enrollment [24].
Timing of dose
● T4 (tablets, gel capsules, or liquid) should be taken on an empty stomach with water, ideally 30 to 60
minutes before breakfast.
● T4 (tablets, gel capsules, or liquid) should not be taken with other meds that interfere with its
absorption (eg, bile acid resins, calcium carbonate, ferrous sulfate). (See "Drug interactions with
thyroid hormones", section on 'Drugs that affect gastrointestinal absorption of thyroid hormone'.)
● Some patients take their T4 at bedtime (at least two hours after their last meal, ideally longer).
Few patients are able to wait a full hour before eating breakfast. The proximity to food ingestion, rather
than time of day, is the more critical parameter. A meta-analysis demonstrated no difference in
effectiveness of morning versus bedtime dosing based on TSH measurements [25]. In some studies, serum
TSH concentrations were lower and less variable with standard fasting administration of T4 than with
nonfasting administration (eg, mean serum TSH 1.06±1.23, 2.93±3.29, and 2.19±2.66 mU/L if taken one
hour before breakfast, with breakfast, or at bedtime two hours after the last meal, respectively) [26,27]. In
another small study, there was no difference in serum TSH levels after ingestion of liquid T4 at breakfast
compared with the same dose 30 minutes prior to breakfast [28]. In two small studies, espresso coffee, in
comparison with water, appeared to interfere with T4 absorption of levothyroxine tablets [29] but not soft
gel capsules [30].
Initial monitoring and dose adjustments — Patients who are treated with T4 usually begin to improve
symptomatically within two weeks, but complete recovery can take several months in those with severe
hypothyroidism. Although symptoms may begin to resolve after two to three weeks, steady-state TSH
concentrations are not achieved for at least six weeks. Serum thyroid hormone concentrations increase
first and then TSH secretion begins to fall because of the negative feedback action of T4 on the pituitary
and hypothalamus.
After initiation of T4 therapy:
● The patient with symptomatic improvement should be re-evaluated and serum TSH measured in four
to six weeks ( algorithm 1). If the TSH remains above the reference range, the dose of T4 can be
increased by 12 to 25 mcg/day in older patients, or it can be increased by a higher dose in younger
patients based on the degree to which the initial dose increased free T4 concentrations and reduced
TSH concentrations. The patient will require a repeat TSH measurement in six weeks. (See 'Adjustment
of maintenance dose' below.)
● The patient with persistent symptoms after two to three weeks should be reevaluated and a serum
free T4 and TSH measured in three weeks. If the serum free T4 is below normal, the dose can be
increased at three weeks without additional testing, but it should be recognized that serum T4 (and
TSH) concentrations at this time are not steady-state values, and serum TSH levels may still be falling
despite normal (or even high) serum T4 concentrations. Given the one-week plasma half-life of T4, it
takes approximately six weeks (six half-lives) before a steady state is attained after therapy is initiated
or the dose is changed.
This process of increasing the dose of T4 every three to six weeks (depending upon the patient's
symptoms) should continue, based upon periodic measurements of serum TSH (and free T4 if steady-state
conditions have not yet been achieved), until the high values of TSH in patients with primary
hypothyroidism return to the reference range. (See 'Goals of therapy' above.)
The maintenance dose may vary according to the cause of hypothyroidism. In a study of patients receiving
chronic T4 therapy who were clinically euthyroid and had serum free T4 index values within the upper half
of the normal range and normal serum TSH concentration, 73 patients with hypothyroidism caused by
chronic autoimmune thyroiditis or radioiodine therapy were receiving less T4 (118 mcg/day, 1.6
mcg/kg/day) than 36 patients with thyroid cancer after near-total thyroidectomy (152 mcg/day, 2.1
mcg/kg/day) [31]. In 36 patients with central hypothyroidism and similar serum free T4 index values, the T4
dose was higher (155 mcg/day, 1.9 mcg/kg/day). These results suggest that both normal amounts of TSH
and the presence of residual thyroid tissue are determinants of T4 dose in patients with hypothyroidism. In
general, doses >2 mcg/kg/day suggest T4 malabsorption or poor adherence to the medication regimen.
(See 'Persistent elevation in TSH' below.)
Adjustment of maintenance dose — After identification of the proper maintenance dose, the patient
should be examined and serum TSH measured once yearly or more often if there is an abnormal result or
a change in the patient's status ( algorithm 1). Further dose adjustment is usually not required, but there
are situations in which a different dose may be needed. When drugs that affect the absorption of T4 are
begun for coexisting medical conditions ( table 1), serum TSH should be measured four to six weeks
later to confirm that the T4 dose is still adequate. The dose should be increased if the serum TSH value is
high. Medications that interfere with T4 absorption should be taken several hours after the T4 dose. (See
"Drug interactions with thyroid hormones", section on 'Drugs that affect gastrointestinal absorption of
thyroid hormone'.)
In addition, increases in dose may be required in the following settings ( table 2):
● Pregnancy, and if increased, the dose should be reduced to the prepregnancy maintenance dose
postpartum. (See "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and
treatment", section on 'Preexisting treated hypothyroidism'.)
● Weight gain of more than 10 percent of body weight.
● Diminished thyroid hormone absorption (patients with impaired acid secretion or other
gastrointestinal disorders [eg, uncontrolled celiac disease]). (See "Diagnosis of celiac disease in
adults".)
● Increased thyroid hormone excretion (nephrotic syndrome). (See "Endocrine dysfunction in the
nephrotic syndrome".)
● Increased rate of thyroid hormone metabolism (therapy with rifampin, carbamazepine, phenytoin, or
phenobarbital). (See "Drug interactions with thyroid hormones", section on 'Drugs that affect thyroid
hormone metabolism'.)
If the TSH is slightly elevated (eg, 5 to 10 mU/L), a small increase of 12 to 25 mcg/day is usually sufficient. If
the TSH is ≥10 mU/L, a larger dose increase (eg, 25 to 50 mcg/day) is usually necessary. Because of the
seven-day half-life of levothyroxine, another method of changing the dose without the need for a new
prescription is to recommend increasing the dose by 15 percent by adding one tablet a week. For example,
if a patient is taking 100 mcg/d (1 tablet a day), if they were to take 8 tablets a week (eg, 1 tablet a day for 6
days and 2 tablets on 1 day), this is equivalent to 114 mcg a day ([(100 x 8)/7 = 114]).
Free T4 measurements can help determine an appropriate dose increase when TSH is very high (eg, ≥20
mU/L) since the magnitude of TSH elevation in hypothyroid patients is quite variable. For example, if
steady-state conditions exist and the TSH exceeds 20, and the free T4 measurement is only half the mean
value of the normal reference range (for example, a free T4 of 0.7 ng/dL in an assay with a normal range of
0.9 to 1.9 ng/dL), the dose could initially be doubled to target a mid-normal free T4 (a free T4 of 1.4 ng/dL
in the example given). If the free T4 measurement is in the lower third of the normal range (for example, a
free T4 1.2 ng/dL in the example above), a 20 percent increase in dose would target a mid-normal free T4.
Further dose adjustments may be needed. The normal range for free T4 is assay dependent, and the
target free T4 level may be higher than the average level, for example, in patients with thyroid cancer.
Decreases in dose may be required in the following settings [32,33]:
● Normal aging
● Weight loss of roughly more than 10 percent of body weight
● Initiation of androgen therapy
If the TSH is slightly below normal (eg, 0.05 to 0.3 mU/L), a small dose reduction of 12 to 25 mcg/day is
usually sufficient. An alternative is to reduce the dose by 15 percent by omitting one pill a week. Lower TSH
values may require larger dose reductions. For TSH values below 0.05 mU/L (below 0.1 mU/L in a second-
generation assay), measurement of free T4 can help determine the estimated dose reduction. For
example, using the free T4 assay described above, if the free T4 is 2.8 ng/dL, which is twice the average
free T4, the necessary dose reduction may be as high as 50 percent if the target is a mid-normal free T4.
However, in young patients with longstanding overtreatment, a stepwise reduction in dose over three to
four months might be better tolerated. When TSH is suppressed to <0.05 mU/L, it will occasionally take
longer than eight weeks for steady-state levels to be re-established.
The serum TSH should be remeasured six to eight weeks after any change in dose. (See 'Goals of therapy'
above.)
Adverse effects — Adverse effects of T4 replacement are rare as long as the correct dose is given. (See
'Over-replacement' below.)
Rare patients have an allergy to the dye or excipients (filler) in the tablets. For dye sensitivities, multiples of
the white 50 mcg tablets can be given. For allergies to excipients (except gelatin), the soft gel capsule
(which contains T4 as a liquid) can be given. The liquid formulation contains glycerol and water.
Long-term outcomes — Successful treatment reverses all the symptoms and signs of hypothyroidism,
although some neuromuscular and psychiatric symptoms may not disappear for several months. Long-
term treatment of hypothyroidism is not associated with impaired cognitive function or depressed mood in
some studies [34], but other studies have documented a persistent defect in psychological well-being that
was not corrected with adequate amounts of T4 [35]. Limited evidence also suggests no increase in all-
cause mortality among patients with treated hypothyroidism [36,37].
In contrast, infants with congenital hypothyroidism in whom treatment is inadequate or delayed for
several months may have permanent brain damage, even if they are adequately treated several months
later. (See "Treatment and prognosis of congenital hypothyroidism".)
Persistent symptoms — Because many symptoms of hypothyroidism are nonspecific, patients often

think that their T4 dose is inadequate when they feel tired or gain weight. The possibility of an inadequate
current T4 dose should be verified by measuring serum TSH before the dose is increased. In addition,
clinicians should evaluate for alternative causes of the symptoms.
The dose of T4 need not be altered in patients who are clinically euthyroid if their serum TSH concentration
is normal or only slightly above (or below) the reference range. TSH values may be slightly high (or low)
because of laboratory error or normal circadian fluctuations in TSH secretion, so a slightly high (or low)
value should be confirmed with repeat measurement before the dose is changed. On the other hand, if a
patient has possible hypothyroid symptoms and the serum TSH is confirmed by repeat measurement to be
at the upper limits or above the reference range, it is reasonable to increase the dose and to aim for a
serum TSH value in the lower half of the reference range. However, it is important to note that there is an
age-related shift towards higher TSH concentrations in older patients, with an upper limit of normal of
approximately 7.5 mU/L in 80 year olds. (See "Laboratory assessment of thyroid function", section on
'Serum TSH'.)
Additionally, it is likely that improved symptoms with higher doses are due to the expectation of feeling
better on a higher dose of levothyroxine, rather than a true physiologic benefit. In one study of 697
patients on thyroid hormone replacement, psychological well-being assessed by the General Health
Questionnaire (GHQ)-12 correlated positively with serum free T4 and negatively with serum TSH for TSH
values between 0.3 to 4.0 mU/L [38]. More specifically, psychological well-being was better in patients with
lower serum TSH concentrations. However, in a blinded, placebo-controlled, crossover trial, patients could
not distinguish between their usual T4 dose and doses that were 25 to 50 mcg/day higher, ie, they could
not distinguish between TSH values that averaged 2.8 mU/L from those that averaged 0.3 mU/L [39], and
in a second double-blinded trial, patients had no preference after varying doses of levothyroxine that
resulted in average TSH levels between 1.85 and 9.49 mU/L [40].
Persistent symptoms of hypothyroidism despite a normal serum TSH level may be due to inadequacy of T4
to physiologically restore tissue thyroid hormone levels to normal or to factors unrelated to
hypothyroidism, such as inflammation in other tissues from autoimmune disease [41].
● The question of whether a subset of hypothyroid patients with persistent symptoms may benefit from
substitution of some T3 (liothyronine) for T4 is reviewed below. (See 'Combination T4 and T3 therapy'
below.)
● The question of whether thyroid peroxidase (TPO) antibodies themselves, or associated immunologic
modulators, cause inflammation in other tissues was evaluated in a trial from Norway, in which 150
patients with Hashimoto's thyroiditis and persistent symptoms (eg, fatigue, joint and muscle
tenderness, dry mouth and eyes) despite normal TSH and free T4 were randomly assigned to total
thyroidectomy or medical management (with optimally titrated thyroid hormone replacement in both
groups) [42]. After 18 months, there was a greater decrease in TPO antibody levels and a greater
improvement in the primary outcome (SF-36 general health score) in the patients who received
surgery (+26 versus -3 points in the medical management group). The absence of a sham surgical
group limits the validity of this study, however it is unlikely that the study can be repeated with an
appropriate control group, and this provocative finding is likely to remain controversial. Thyroidectomy
has surgical complications (in this trial, infection [4.1 percent], hypocalcemia [4.1 percent], and
recurrent laryngeal nerve palsy [5.5 percent]) and is currently not a recommended treatment for
autoimmune-mediated thyroiditis.
Persistent elevation in TSH — Occasionally a patient will insist they are taking T4, but TSH will be quite
high. Often these patients are taking larger doses of T4 than expected. This finding may be due to poor
compliance or to poor absorption of T4.
Patients with autoimmune gastritis have higher T4 requirements (especially tablet preparations). In one
study, the T4 dose was 17 percent higher in patients with parietal cell antibodies [43]. A similar effect can
be seen in patients with occult celiac disease [44]. In this setting, free T4 levels are typically low or low-
normal. In contrast, poorly compliant patients may have free T4 concentrations that are low, normal, or
high, depending on how much T4 they have taken and when they have taken it (some poorly compliant
patients take extra T4 in the days leading up to the appointment with their clinician and may have a high-
normal or even an elevated free T4 with a TSH that hasn't had time to fall into the normal or subnormal
range).
In patients with persistently elevated TSH despite what appears to be an adequate dose of T4, it should be
confirmed that T4 is taken daily on an empty stomach with water, ideally an hour before breakfast, and
that medications that interfere with T4 absorption ( table 1) are taken several hours after the T4 dose.
If the TSH remains elevated, and noncompliance is not acknowledged, adequate T4 absorption can be
assessed by a T4 absorption test. Patients are administered their weight-based weekly oral dose of T4 (eg,
1.6 mcg/kg body weight times 7), and free T4 is measured at baseline and at two hours. In one study, the
average normal increase in free T4 at 120 minutes was 54 percent [45]. Values well below this suggest
malabsorption, whereas values similar to this suggest poor compliance. Only 1 of 16 tests done at one
institution over a four-year period documented malabsorption [46]. (See 'Poorly compliant patients' below.)
In patients with celiac disease, a gluten-free diet improves T4 absorption [44]. Other options for patients
with poor T4 absorption include increasing the dose of T4 tablets or switching to a soft gel or liquid
preparation. In one study, patients who appeared to be resistant to levothyroxine administration did not
absorb T4 tablets well but absorbed T4 tablets after they were pulverized [47]. (See 'T4 formulations'
above.)
Over-replacement — Over-replacement with T4 should be discouraged. Over-replacement causes

subclinical hyperthyroidism (normal serum T4 and T3 and low serum TSH concentrations) or even overt
hyperthyroidism. Atrial fibrillation is the main risk of subclinical hyperthyroidism, and it occurs three times
more often in older patients with serum TSH concentrations <0.1 mU/L than in normal subjects ( figure 1
) [48]. Patients with iatrogenic subclinical hyperthyroidism, particularly postmenopausal women, may also
have accelerated bone loss. It is therefore important to educate patients about the potential adverse
effects of overtreatment with T4. (See "Bone disease with hyperthyroidism and thyroid hormone therapy".)
The risks associated with over-replacement of thyroid hormone are greatest in those with the most
suppressed TSH concentrations. This was illustrated by the findings from a cohort study of 17,684 patients
taking T4 replacement therapy. Patients with TSH concentrations between 0.04 and 0.4 mU/L were not at
risk for arrhythmias or fractures compared with those with a TSH in the normal reference range. However,
patients with more severe iatrogenic thyrotoxicosis (TSH <0.03 mU/L) had a significantly increased risk of
arrhythmia (hazard ratio [HR] 1.6) and fractures (HR 2.0) [49]. (See 'Adjustment of maintenance dose'
above.)
COMBINATION T4 AND T3 THERAPY
Is there a role for T3? — For the vast majority of patients with hypothyroidism, we suggest not using
combination T4-T3 therapy. However, a therapeutic trial using doses of T4 and T3 that attempt to mimic
normal physiology (ratio T4-to-T3 of 13:1 to 16:1) while maintaining a normal TSH is an option in selected
patients. (See 'Candidates for combined T4 and T3 therapy' below.)
There is controversy as to whether T4 replacement alone can mimic normal physiology. T4 is deiodinated
in peripheral tissues to form T3, the active thyroid hormone. The prohormone nature of T4 is an advantage
over other thyroid hormone preparations because the patient's own physiologic mechanisms control the
production of active hormone. In some [12,50], but not all [51,52], studies, mean serum T3 concentrations
were within the normal range in hypothyroid patients receiving adequate T4 therapy. In a prospective
study of recently athyreotic patients receiving T4 therapy to normalize serum TSH concentrations, serum
T3 concentrations on treatment were, in most, but not all cases, comparable with the patients'
preoperative T3 values [50]. However, in another study, 15 percent of athyreotic patients taking T4
monotherapy had serum T3 levels below the reference range for individuals with intact thyroid glands [52].
Some hypothyroid patients remain symptomatic in spite of T4 replacement and normal serum TSH
concentrations [53]. In a large, community-based questionnaire study of patients taking T4 who had
normal serum TSH concentrations, 9 to 13 percent more patients had impaired psychological well-being as
compared with normal subjects [35]. This observation raises the question of whether hypothyroid patients
might benefit from substitution of some T3 for T4, an idea that has now been evaluated in multiple
randomized trials, almost all of which showed that combination T4-T3 therapy does not appear to be
superior to T4 monotherapy for the management of hypothyroid symptoms [54-65]. (See 'Efficacy' below.)
Well-designed, blinded studies are still needed to address this ongoing controversy [66]. The normal ratio
of T4-to-T3 secretion by the thyroid gland is approximately 13:1 to 16:1 (mcg T4 to mcg T3) [41]. The
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majority of the randomized, controlled trials used excessive and nonphysiologic amounts of T3 when
assessing combination therapy. In addition, a slow-release T3 preparation, which may avoid
supraphysiologic peaks in serum T3 concentrations, is not yet commercially available [67]. A combination
T4-slow release T3 preparation may better replicate physiologic T4-T3 production.
Efficacy — In a systematic review of nine randomized trials, only one trial reported beneficial effects of
combination T4-T3 therapy on mood, quality of life, and psychometric performance when compared with
T4 therapy alone [68]. A subsequent meta-analysis of 11 published randomized trials including 1216
patients showed that there was no benefit (fatigue, bodily pain, anxiety, depression, quality of life) of
combined therapy [69].
In some trials, patients preferred combined therapy to T4 monotherapy [70]. In some [63], but not all
[61,71], of these trials, patients were given overzealous doses of T3, resulting in mild hyperthyroidism. As
examples:
● In one trial comparing T4 alone with T4 and T3 in a molar ratio of 10:1 or 5:1, there were similar
improvements in mood, fatigue, psychological symptoms, or neurocognitive testing [63]. However,
patients preferred combined therapy to T4 alone. Forty-four percent of the patients who preferred
combined therapy had TSH values less than 0.11 mU/L. In addition, those patients taking T4:T3 in a
molar ratio of 5:1 had a 1.8 kg weight loss, which correlated with a preference for the combined
treatment, and 54 percent of these patients had subnormal serum TSH concentrations.
● In one small, well-designed study, women taking 100 mcg of T4 were changed to 75 mcg T4 and 5 mcg
T3 (ratio 15:1) [61]; while no benefit was found using standardized questionnaires, patients preferred
combination therapy over monotherapy despite a higher TSH within the normal range in the group
receiving combination therapy.
● In a double-blind, crossover trial comparing T4 and desiccated thyroid extract (T4-to-T3 ratio 4:1), there
were no differences in symptoms and neurocognitive measurements between the two groups, but 49
percent of the patients preferred thyroid extract over T4 (19 percent preferred T4 and 33 percent had
no preference), and those who preferred thyroid extract had lost on average 1.8 kg during the study
[71]. In this trial, thyroid medications were adjusted to maintain a TSH level between 0.5 and 3.0 mU/L
(mean achieved TSH levels were 1.30 and 1.67 mU/L for T4 and desiccated thyroid extract,
respectively).
Whether a combination of T4 and T3 is beneficial in a subset of hypothyroid patients has also been
studied. One analysis suggested patients with a polymorphism in the type 2 deiodinase, which converts T4
to T3, might benefit from combination therapy [72]. Sixteen percent of the population studied had the CC
genotype of the rs225014 polymorphism in the deiodinase 2 gene (DIO2); these patients had worse
baseline quality-of-life scores and showed greater improvement after T4-T3 therapy compared with T4
alone. However, a smaller study was unable to show a difference in response to combined T4-T3 therapy
based on DIO2 genotype [73]. In addition, a large population-based study showed lower health-related
quality-of-life scores in levothyroxine-treated hypothyroid patients compared with controls, but this did not
differ among individuals who did or did not have the rs225014 polymorphism [74].
Some thyroidectomized patients who have no residual endogenous T3 production might derive benefit
from the addition of T3. In one study, serum T3 levels were more uniformly restored to preoperative levels
when T4 doses were high enough to suppress the serum TSH (≤0.3 mU/L) [51]. However, in another study,
traditional T4 therapy that resulted in a TSH level of ≤4.6 mU/L resulted in normal T3 levels in most but not
all patients [50].
Candidates for combined T4 and T3 therapy — The majority of patients do well on T4 monotherapy,

and we do not suggest the routine use of combined T4 and T3 therapy for the treatment of
hypothyroidism. This is in agreement with the 2014 American Thyroid Association (ATA) guidelines, which
found insufficient evidence to support the routine use of a combination of T4 and T3 therapy in patients
unhappy with T4 monotherapy [1].
However, a therapeutic trial using doses of T4 and T3 that attempt to mimic normal physiology (ratio T4-to-
T3 of 13:1 to 16:1) while maintaining a normal TSH is reasonable in selected patients. Candidates for
combined therapy include patients who have not felt well on T4 monotherapy:
● Since thyroidectomy
● Since ablative therapy with radioiodine
Or
● Who have serum T3 at or below the lower end of the T3 reference range
Patients who have previously felt well on T4 monotherapy but now feel poorly and patients with mild
hypothyroidism on low doses of T4 who have persistent endogenous thyroid function are not likely to
improve with combined therapy. In addition, we discourage the use of combined therapy in older patients,
patients with underlying cardiovascular disease in whom excessive T3 levels might precipitate an
arrhythmia, and in pregnant women.
An important caveat for women of childbearing age using combined T4 and T3 treatment is that fetal
neurogenesis is primarily dependent upon maternal free T4 concentrations until week 16 to 18 of
gestation [75]. Regimens containing excessive T3 cause hypothyroxinemia, which has been associated with
impaired neurologic development. For example, patients taking desiccated thyroid extract in the trial
noted above [71] had a mean free T4 of 0.85 ng/dL (normal 0.89 to 1.76 ng/dL).
Temporary treatment with T3 monotherapy is appropriate in patients with thyroid cancer who are to
undergo radioiodine imaging and possible treatment. To shorten the period of hypothyroidism, the
patient's T4 therapy is discontinued, and T3 is substituted for three to four weeks until the T4 is cleared.
(See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Thyroid hormone withdrawal'.)
Dosing and available preparations — There are several commercial thyroid hormone preparations
containing T3 alone or in combination with T4 ( table 3).
● We do not use combined T4 and T3 therapy when the ratio of T4 to T3 is not physiologic (ie, when T3
doses are excessive). The normal ratio of T4-to-T3 of 13:1 to 16:1.
● We do not use desiccated thyroid extract, which has a T4-to-T3 ratio of 4:1. (See 'Converting from
desiccated thyroid extract to T4' below.)
Although for most patients with hypothyroidism we do not suggest treatment with T3, if combined therapy
is given, the doses of T4 and T3 should mimic normal physiology as closely as possible. T3 alone is
available as 5 and 25 mcg tablets, so available doses utilizing half tablets are 2.5, 5, 7.5, 10, and 12.5 mcg.
When possible, the dose of T3 should be divided into morning and afternoon doses. One can calculate an
optimal dose by considering that T3 is three to four times more potent metabolically than T4 and aiming
for a T4-to-T3 ratio of approximately 13:1 to 16:1 [41]. The table is offered as a guide for the conversion of
T4 monotherapy to combined T4 and T3 therapy ( table 4). This approach is consistent with the European
Thyroid Association (ETA) guidelines on the use of combination therapy, published with the intent of
enhancing its safety [41].
Monitoring combined therapy — In patients taking combined therapy, we typically monitor TSH six
weeks after initiating therapy. TSH levels in steady-state conditions will reflect adequacy of therapy. Serum
free T4 can be useful, especially in non-steady-state conditions, in patients receiving combined T4 and T3
therapy at a physiologic ratio of 13:1 to 16:1 but may be misleading (due to low values) in patients
receiving combined therapy where the ratio is low. For example, over half of patients receiving desiccated
thyroid extract (T4:T3 ratio 4:1) will have subnormal T4 concentrations despite normal serum TSH [71].
We do not monitor T3 levels. Patients treated with currently available T3-containing preparations have
wide fluctuations in serum T3 concentrations throughout the day due to its rapid gastrointestinal
absorption and its relatively short half-life in the circulation (approximately one day). In fact, T3 serum
levels may be elevated three to four hours after the last dose (eg, at noon if the dose is taken at 8 AM) and
low if T3 is measured before the next dose. Thus, T3 measurements primarily reflect the interval since the
dose was administered and should not be used for monitoring.
Converting from desiccated thyroid extract to T4 — For patients who are taking desiccated thyroid,
we prefer to switch them to T4.
By US Food and Drug Administration (FDA) mandate, 1 grain of desiccated thyroid extract (60 mg) should
contain approximately 38 mcg T4 and 9 mcg T3. Using a conversion of 9 mcg T3 is equivalent to
approximately 36 mcg T4, 1 grain would be equivalent to approximately 74 mcg T4. However, in a
randomized trial comparing T4 with desiccated thyroid extract, 1 grain (60 mg) of extract was equivalent to
88 mcg of T4 [71]. Both of these conversions result in lower amounts of T4 than traditionally
recommended; the United States Pharmacopeia Drug Information suggests 1 grain (60 mg) is equivalent
to 100 mcg [71]. Thus, many clinicians use a simple conversion factor of 1 grain = 100 mcg T4. For a patient
who is taking 1.5 grains (90 mg) of desiccated thyroid, an equivalent T4 dose ranges from 112 to 150 mcg.
Some clinicians prefer to begin with the higher dose (150 mcg) and slowly taper the dose if the TSH
measured six weeks after switching remains below the reference range.
Converting from combined T4 and T3 therapy to T4 monotherapy — For patients converting from

T4-T3 combination preparations back to T4 monotherapy, the equivalent dose of T4 can be calculated by
considering that T3 is three to four times more potent metabolically than T4. As an example, for a patient
who is taking a preparation of 12.5 mcg T3 combined with 50 mcg T4, the equivalent dose of T4 is
approximately 100 mcg (50 mcg T4 plus four times the dose of T3).
SPECIAL TREATMENT SITUATIONS
There are several situations in which therapy should be more conservative or the dose may need
modification:
Older patients or those with coronary heart disease — Older patients (>60 years), patients with
coexisting cardiopulmonary problems, or patients with a history of coronary heart disease, should initially
be treated with 25 to 50 mcg T4 (levothyroxine)/day ( algorithm 1). Patients with coronary artery disease
without other cardiopulmonary problems who have had recent successful interventions to treat ischemia
(eg, coronary artery bypass grafting [CABG] or coronary artery stenting) can initially receive up to 80
percent of their weight-based dose (1.6 mcg/kg/day).
The dose can be increased by 12 to 25 mcg/day every three to six weeks until replacement is complete, as
determined by a normal serum TSH concentration or an increase in dose results in cardiac symptoms, in
which case something less than full replacement may have to be accepted. It is important to note that
there is an age-related shift towards higher TSH concentrations in older patients, with an upper limit of
normal of approximately 7.5 mU/L in 80 year olds. (See 'Goals of therapy' above.)
Thyroid hormone increases myocardial oxygen demand, which is associated with a small risk of inducing
cardiac arrhythmias, angina pectoris, or myocardial infarction in older patients. A 1961 report remains the
largest and best study of the effects of beginning thyroid hormone on chest pain in patients with
hypothyroidism [76,77]. Among 1503 hypothyroid patients, the following findings were noted:
● Fifty-five had angina before thyroid hormone replacement therapy. During therapy, 21 improved, 25
had no change, and 9 had more angina.
● Thirty-five patients developed new angina during therapy, 6 during the first month, 6 during the first
year, and 23 after one year.
Thus, angina may improve with T4 treatment, and it does not often first appear during T4 replacement
therapy.
Many older patients receiving thyroid hormone replacement are over- or undertreated, as illustrated by a
community survey that identified 339 individuals over age 65 years taking thyroid hormone [78]. Forty-one
percent of patients had a subnormal TSH, 16 percent had a high TSH, and only 43 percent were euthyroid
[78]. Patients with low body weight were more likely to have a subnormal TSH, while those with diabetes
were at risk for having low and high serum TSH. (See 'Goals of therapy' above.)
The clinical manifestations and consequences of hypothyroidism (subclinical and overt) in older adults are
discussed in detail elsewhere. (See "Clinical manifestations of hypothyroidism" and "Subclinical
hypothyroidism in nonpregnant adults", section on 'Consequences of subclinical hypothyroidism'.)
Pregnancy — Women need more thyroid hormone during pregnancy and, unlike normal women, those
with hypothyroidism are unable to increase thyroidal T4 and T3 secretion. Approximately 75 to 85 percent
of women with preexisting hypothyroidism need a higher dose of T4 during pregnancy to maintain normal
TSH secretion. The increase in T4 requirements occurs as early as the fifth week of gestation and plateaus
by week 16 to 20. The treatment of hypothyroidism during pregnancy is reviewed separately. (See
"Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment", section on
'Preexisting treated hypothyroidism'.)
Euthyroid women with TPO antibodies who become pregnant are also discussed separately. (See
"Overview of thyroid disease and pregnancy", section on 'Thyroid peroxidase antibodies in euthyroid
women'.)
Estrogen therapy — In women receiving T4 therapy, estrogens increase serum thyroxine-binding globulin
(TBG) concentrations, as they do in normal women, and may increase the need for T4. In a study of
postmenopausal women (25 women with hypothyroidism and 11 normal women) treated with 0.625 mg
conjugated estrogens daily for 48 weeks, serum T4 and TBG concentrations increased in both the
hypothyroid and normal women. Serum free T4 and TSH concentrations did not change in the normal
women but decreased and increased, respectively, in the hypothyroid women [79]. Among the latter, seven
women had serum TSH concentrations >7 mU/L and were given more T4. These data suggest that serum
TSH should be measured approximately 6 to 12 weeks after starting estrogen therapy in postmenopausal
women receiving T4 therapy to determine if an increase in T4 dose is needed. Whether younger
hypothyroid women receiving oral contraceptives require dose adjustments is uncertain. Such patients
may require dose adjustments, especially when oral contraceptives are initiated because of
hypoestrogenic states.
Surgical patients — Patients receiving chronic T4 therapy who undergo surgery and are unable to eat for
several days need not be given T4 parenterally. If oral intake cannot be resumed in five to seven days, then
T4 should be given intravenously. The dose should be approximately 70 to 80 percent of the patient's usual
oral dose because that is approximately the fraction of oral T4 that is absorbed [12,80]. We typically give 80
percent.
Several studies have investigated the safety of general anesthesia and surgery in patients with untreated
or inadequately treated hypothyroidism. This topic is reviewed in detail elsewhere. (See "Nonthyroid
surgery in the patient with thyroid disease", section on 'Hypothyroidism'.)
Poorly compliant patients — Some patients do not take their T4 regularly and do not respond to efforts
to improve compliance. These patients may be given their total weekly dose of T4 once per week. The
efficacy of this approach was evaluated in a crossover trial of 12 patients [81]. The mean serum TSH
concentration one week after a single weekly dose was slightly higher than when the usual dose was given
daily (6.6 versus 3.9 mU/L), but the raised value returned to normal one day after the next weekly dose.
There was no difference in symptoms between daily or weekly dosing. Weekly dosing should probably not
be used in patients with coronary heart disease.
Thyroid cancer — Patients who have had a thyroidectomy for thyroid cancer, with or without additional
treatment with radioiodine (I-131), need to take T4 not only for treatment of hypothyroidism but also to
prevent recurrence of their thyroid cancer, especially those with higher risk disease. (See "Differentiated
thyroid cancer: Overview of management", section on 'Thyroid hormone suppression'.)
Myxedema coma — Myxedema coma is defined as severe hypothyroidism leading to decreased mental

status, hypothermia, and other symptoms. It is a medical emergency with a high mortality rate.
Fortunately, it is now a rare presentation of hypothyroidism, probably because of earlier diagnosis. The
clinical presentation, diagnosis, and treatment of myxedema coma are reviewed separately. (See
"Myxedema coma".)
Selenium deficiency — Selenium is required for deiodinase activity (the enzyme is a selenoprotein), and it
has important effects on immune function. The effects of selenium deficiency on normal thyroid function
are not well described. However, selenium deficiency has been shown to exacerbate both autoimmune
thyroid disease and endemic cretinism [82]. Selenium supplementation in some studies reduces
antithyroid peroxidase antibody levels, improves the ultrasound structure of the thyroid gland, and
reduces the occurrence of postpartum thyroiditis in pregnant women with TPO antibodies, but a meta-
analysis failed to show any improvement in thyroid function when selenium is given to hypothyroid
individuals [83]. (See "Postpartum thyroiditis", section on 'Prevention'.)
When the diagnosis of hypothyroidism is uncertain — Some patients have been prescribed thyroid
hormone for questionable indications (eg, obesity or hypercholesterolemia) or the diagnosis of
hypothyroidism is uncertain. In such a patient, a high serum TSH concentration suggests that the patient is
hypothyroid, and the T4 dose should be increased accordingly. If, however, the serum TSH values are
normal or low, the dose of thyroid hormone can be reduced by one-half and serum TSH measured again in
four to six weeks. If the value is normal, the dose can be reduced further or stopped. Most patients with
hypothyroidism have symptoms and a high serum TSH concentration within one month after
discontinuing therapy. In a meta-analysis of 1082 patients from 16 studies, 37 percent of putatively
hypothyroid patients had their levothyroxine successfully discontinued [84].
Many of these patients are reluctant to discontinue their thyroid hormone, especially if they have taken it
for many years. In the meta-analysis noted above, two-thirds of patients restarted levothyroxine [84]. In
this case, the goal should be to provide an appropriate dose of T4 (adjusted to maintain a normal serum
TSH concentration) to avoid the potential adverse cardiac and skeletal effects of overtreatment.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the
world are provided separately. (See "Society guideline links: Hypothyroidism".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they
answer the four or five key questions a patient might have about a given condition. These articles are best
for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These articles are written at
the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Hypothyroidism (underactive thyroid) (The Basics)")
● Beyond the Basics topics (see "Patient education: Hypothyroidism (underactive thyroid) (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS
● Overt primary hypothyroidism is characterized biochemically by a high serum thyroid-stimulating

hormone (TSH) concentration and a low serum free thyroxine (T4) concentration. All patients with
overt primary hypothyroidism require treatment (regardless of symptoms), unless the hypothyroidism
is transient (as after painless thyroiditis or subacute thyroiditis) or reversible (due to a drug that can be
discontinued). (See 'Defining hypothyroidism' above and "Disorders that cause hypothyroidism",
section on 'Transient hypothyroidism'.)
● The goals of therapy are amelioration of symptoms, normalization of TSH secretion, reduction in size
of goiter (if present), and avoidance of overtreatment (iatrogenic thyrotoxicosis). We aim to keep
serum TSH within the normal reference range (approximately 0.5 to 5.0 mU/L). It is important to note
that there is an age-related shift towards higher TSH concentrations in older patients, with an upper
limit of normal of approximately 7.5 mU/L in 80 year olds. (See 'Goals of therapy' above.)
● The treatment of choice for correction of hypothyroidism is synthetic thyroxine (T4, levothyroxine). For
the vast majority of patients with hypothyroidism, we suggest not using combination T4-
triiodothyronine (T3) therapy (Grade 2B). However, T4-T3 therapy may improve symptoms in selected
patients (eg, after thyroidectomy or ablative therapy with radioiodine). We discourage the use of
combined therapy in older patients, patients with underlying cardiovascular disease in whom
excessive T3 levels might precipitate an arrhythmia, and in pregnant women. (See 'Standard
replacement therapy' above and 'Candidates for combined T4 and T3 therapy' above.)
When T4-T3 therapy is used, the T4-to-T3 ratio should be approximately 13:1 to 16:1 ( table 4). (See
'Dosing and available preparations' above.)
● We suggest that patients remain on the same formulation of T4 (Grade 2C). Either a generic or a
brand-name formulation is acceptable. If a switch from one manufacturer to another is made by the
pharmacy and the patient is concerned regarding equivalent efficacy of the preparations, we measure
a serum TSH six weeks after changing preparations to document that the serum TSH is still within the
therapeutic target. (See 'T4 formulations' above.)
● The initial dose can be the full anticipated dose (1.6 mcg/kg/day) in young, healthy patients, but older
patients and those with coronary heart disease should be started on a lower dose (25 to 50 mcg daily) (
algorithm 1). T4 should be taken on an empty stomach, ideally 30 to 60 minutes before breakfast.
(See 'Initial dose' above and 'Timing of dose' above.)
● After initiation of T4 therapy, the patient should be reevaluated and serum TSH should be measured in
six weeks and the dose adjusted accordingly. Symptoms may begin to resolve after two to three
weeks, but steady-state TSH concentrations are not achieved for at least six weeks. (See 'Initial
monitoring and dose adjustments' above.)
● If a patient has possible hypothyroid symptoms and the serum TSH is confirmed by repeat
measurement to be at the upper limits or above the reference range, it is reasonable to increase the
dose and to aim for a serum TSH value in the lower half of the normal range; however, improved
symptoms with higher doses may be based on expectation of benefit rather than a true physiologic
advantage. (See 'Persistent symptoms' above.)
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Topic 7855 Version 34.0
GRAPHICS
Initial management of primary hypothyroidism in adults
This algorithm depicts an approach to the initial treatment of primary hypothyroidism, defined as a high TSH and a low free T4. The algorithm is not
intended for use in patients with transient hypothyroidism (eg, postpartum thyroiditis) or central hypothyroidism. In central hypothyroidism, serum
TSH levels are typically low or inappropriately normal, but TSH may be slightly elevated due, in part, to the secretion of TSH that has reduced
biologic activity but normal immunoactivity. Refer to other UpToDate content on thyroiditis and central hypothyroidism.
TSH: thyroid-stimulating hormone; ULN: upper limit of normal; T4: thyroxine.
* Assumes adherence to medication regimen.
¶ There is an age-related shift towards higher TSH concentrations in older patients, with a ULN of approximately 7.5 mU/L in 80 year olds. Older patients with
a TSH up to 7.5 mU/L may not require a dose increase, and treatment resulting in TSH levels under 1 mU/L should be avoided.
Δ Symptoms of hypothyroidism may include cold intolerance, fatigue, constipation. Symptoms of hyperthyroidism may include palpitations, heat intolerance,
tremulousness. Refer to UpToDate topics on clinical manifestations of hypothyroidism and hyperthyroidism.
Graphic 131462 Version 1.0
Drugs that cause hypothyroidism, hyperthyroidism, or changes in thyroid function tests
Drugs causing hypothyroidism

Inhibition of thyroid hormone synthesis and/or release – thionamides, lithium, perchlorate, aminoglutethimide, thalidomide, and iodine and
iodine-containing drugs including amiodarone, radiographic agents, expectorants (eg, guaifenesin), kelp tablets, potassium iodine solutions
(SSKI), Betadine douches, topical antiseptics
Decreased absorption of T4 – cholestyramine, colestipol, colesevelam, aluminum hydroxide, calcium carbonate, sucralfate, iron sulfate, raloxifene,
omeprazole, lansoprazole, and possibly other medications that impair acid secretion, sevelemer, lanthanum carbonate, and chromium;
malabsorption syndromes can also diminish T4 absorption
Immune dysregulation – interferon alfa, interleukin-2, ipilimumab, alemtuzumab, pembrolizumab, nivolumab
Suppression of TSH – dopamine
Destructive thyroiditis – TKIs (eg, sunitinib, sorafenib); checkpoint inhibitors (eg, nivolumab, pembrolizumab, and ipilimumab)
Increased type 3 deiodination – TKIs (eg, sorafenib)
Increased T4 clearance and suppression of TSH – bexarotene
Drugs causing hyperthyroidism

Stimulation of thyroid hormone synthesis and/or release – iodine, amiodarone
Immune dysregulation – interferon alfa, interleukin-2, ipilimumab, alemtuzumab, pembrolizumab
Drugs causing abnormal thyroid function tests without thyroid dysfunction

Low serum TBG – androgens, danazol, glucocorticoids, slow-release niacin (nicotinic acid), L-asparaginase
High serum TBG – estrogens, tamoxifen, raloxifene, methadone, 5-fluouracil, clofibrate, heroin, mitotane
Decreased T4 binding to TBG – salicylates, salsalate, furosemide, heparin (via free fatty acids), certain NSAIDs
Increased T4 clearance – phenytoin, carbamazepine, rifampin, phenobarbital
Suppression of TSH secretion – dobutamine, glucocorticoids, octreotide
Impaired conversion of T4 to T3 – amiodarone, glucocorticoids, contrast agents for oral cholecystography (eg, iopanoic acid), propylthiouracil,
propanolol, nadolol
SSKI: saturated solution of potassium iodide; T4: thyroxine; TSH: thyroid-stimulating hormone; TKIs: tyrosine kinase inhibitors; TBG: thyroxine-binding
globulin; NSAIDs: nonsteroidal anti-inflammatory drugs; T3: triiodothyronine.
Factors that increase the requirement for T4
Pregnancy
Estrogen therapy
Weight gain
Drugs that increase catabolism of T4

Rifampin
Carbamazepine
Phenytoin
Phenobarbital
Imatinib
Malabsorption or increased excretion of T4

Gastrointestinal disorders (eg, celiac disease)
Impaired acid secretion
Drugs that interfere with T4 absorption
Ferrous sulfate
Cholestyramine or colestipol
Sucralfate
Aluminum hydroxide gels
Calcium carbonate
Sertraline
Raloxifene
Omeprazole
Nephrotic syndrome
Progressive thyroid dysfunction

Autoimmune thyroiditis
Previous thyroid irradiation
T4: thyroxine.
Modified with permission from: Roberts, CG, Ladenson, PW. Hypothyroidism. Lancet 2004; 363:793. Copyright © 2004 Elsevier.
Increased incidence of atrial fibrillation in subclinical

hyperthyroidism
Cumulative incidence of atrial fibrillation in subjects over age 60 years according to the

serum concentration of TSH. The risk of atrial fibrillation was increased almost
threefold in the subjects with marked suppression of TSH (left panel) as compared with
those who had normal serum TSH concentrations and were presumably euthyroid
(right panel); patients with slightly low serum TSH concentrations (middle panel) had a
lesser increase in risk.
TSH: thyroid-stimulating hormone.
Data from: Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor
for atrial fibrillation in older persons. N Engl J Med 1994; 331:1249.
Characteristics of oral thyroid hormone preparations available in the United States
Average adult dose/day

Generic name Composition Brand names*
(oral)
Levothyroxine ¶ T4 Tablets Δ: Euthyrox, Levo-T, 112 to 125 mcg

Levoxyl, Synthroid, Unithroid
Soft gel capsules ◊: Tirosint
Oral solutions §: Tirosint-Sol,

Thyquidity
Liothyronine T3 Cytomel ¥ 37.5 mcg
Desiccated thyroid extract

4:1 mixture of T4 and T3 Armour Thyroid, Nature-Throid ‡, 90 mg
(Thyroid USP) (approximately) NP Thyroid, WP Thyroid ‡
1 grain of desiccated thyroid

extract (60 mg) should contain
approximately 38 mcg T4 and 9
mcg T3
Pork or beef origin
T3: triiodothyronine; T4: thyroxine.
* Generic preparations of levothyroxine and liothyronine are also available.
¶ Best preparation.
Δ Available in tablet strengths from 25 to 300 mcg.
◊ Available in capsule strengths from 13 to 200 mcg.
§ Tirosint-Sol is supplied in 1 mL unit dose ampules of varying concentrations from 13 to 200 mcg/mL. Thyquidity is available as a 100 mcg/5 mL oral
solution in a 100 mL bottle.
¥ Available in tablet strengths of 5, 25, and 50 mcg.
‡ In September 2020, all lots of Nature-Throid (previously called Westhroid) and WP Thyroid were voluntarily recalled because certain lots contained less
levothyroxine than the labeled amount. The manufacturer has not announced when product will be available.
Approach to conversion of T4 monotherapy to combined T4 and T3 therapy [1]
Combined T4 and T3 oral therapy reflecting a physiologic T4-to-T3 ratio of

Current T4 therapy (mcg/day) 13:1 to 16:1*
T4 oral dose (mcg/day) T3 dose
75-100 50-75 2.5 mcg twice daily
112-137 88-112 2.5 mcg three times daily or

5 mcg AM and 2.5 mcg PM
150-175 112-137 5 mcg twice daily
200-250 150-200 7.5 mcg AM and 5 mcg PM
For patients in whom combined T4 and T3 therapy is pursued, the T4 and T3 components should be prescribed as separate levothyroxine and
liothyronine pills according to the above conversions, which provide T4:T3 in a dose ratio that approximates normal physiology. Refer to
UpToDate topic on treatment of primary hypothyroidism in adults for details, including patient selection considerations.
T4: levothyroxine; T3: liothyronine.
* Commercially available T4-T3 combination pills (liotrix) are a 4:1 ratio mixture that deliver a supraphysiologic T3 dose relative to T4 and are not suitable
for providing a T4:T3 dose ratio that approximates the physiologic ratio shown in this table.
Reference:
1. Wiersinga WM, Duntas L, Fadeyev V, et al. 2012 ETA guidelines: The use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J 2012; 1:55.

Courtesy of Douglas S Ross, MD.

Treatment of Primary Hypothyroidism in Adults - UpToDate

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29/7/2021 Treatment of primary hypothyroidism in adults - UpToDate

Reimpresión oficial de UpToDate ®

Tratamiento del hipotiroidismo primario en adultos

● (Ver "Hipotiroidismo subclínico en adultos no embarazadas" ).

ENFOQUE DEL TRATAMIENTO

● El hipotiroidismo primario manifiesto se caracteriza bioquímicamente por una concentración sérica

deficiencia de hormona tiroidea. (Consulte "Manifestaciones clínicas del hipotiroidismo" y "Diagnóstico

● Central hypothyroidism caused by hypothalamic or pituitary disease is characterized by a low serum

Goals of therapy — The goals of therapy are:

STANDARD REPLACEMENT THERAPY

Dose and monitoring

After initiation of T4 therapy:

● Weight gain of more than 10 percent of body weight.

Decreases in dose may be required in the following settings [32,33]:

Persistent symptoms — Because many symptoms of hypothyroidism are nonspecific, patients often

Over-replacement — Over-replacement with T4 should be discouraged. Over-replacement causes

COMBINATION T4 AND T3 THERAPY

Candidates for combined T4 and T3 therapy — The majority of patients do well on T4 monotherapy,

Converting from combined T4 and T3 therapy to T4 monotherapy — For patients converting from

SPECIAL TREATMENT SITUATIONS

Myxedema coma — Myxedema coma is defined as severe hypothyroidism leading to decreased mental

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

● Overt primary hypothyroidism is characterized biochemically by a high serum thyroid-stimulating

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Topic 7855 Version 34.0

Initial management of primary hypothyroidism in adults

TSH: thyroid-stimulating hormone; ULN: upper limit of normal; T4: thyroxine.

* Assumes adherence to medication regimen.

Graphic 131462 Version 1.0

Drugs that cause hypothyroidism, hyperthyroidism, or changes in thyroid function tests

Drugs causing hypothyroidism

Immune dysregulation – interferon alfa, interleukin-2, ipilimumab, alemtuzumab, pembrolizumab, nivolumab

Suppression of TSH – dopamine

Increased type 3 deiodination – TKIs (eg, sorafenib)

Increased T4 clearance and suppression of TSH – bexarotene

Drugs causing hyperthyroidism

Immune dysregulation – interferon alfa, interleukin-2, ipilimumab, alemtuzumab, pembrolizumab

Drugs causing abnormal thyroid function tests without thyroid dysfunction

Increased T4 clearance – phenytoin, carbamazepine, rifampin, phenobarbital

Suppression of TSH secretion – dobutamine, glucocorticoids, octreotide

Graphic 50439 Version 12.0

Factors that increase the requirement for T4

Drugs that increase catabolism of T4

Malabsorption or increased excretion of T4

Progressive thyroid dysfunction

Graphic 60325 Version 3.0

Increased incidence of atrial fibrillation in subclinical

Cumulative incidence of atrial fibrillation in subjects over age 60 years according to the

TSH: thyroid-stimulating hormone.

Graphic 55024 Version 4.0

Characteristics of oral thyroid hormone preparations available in the United States

Average adult dose/day

Levothyroxine ¶ T4 Tablets Δ: Euthyrox, Levo-T, 112 to 125 mcg

Soft gel capsules ◊: Tirosint

Oral solutions §: Tirosint-Sol,

Liothyronine T3 Cytomel ¥ 37.5 mcg

Desiccated thyroid extract

1 grain of desiccated thyroid

Pork or beef origin

T3: triiodothyronine; T4: thyroxine.

* Generic preparations of levothyroxine and liothyronine are also available.