Treatment of Primary Hypothyroidism in Adults - UpToDate
Treatment of Primary Hypothyroidism in Adults - UpToDate
Treatment of Primary Hypothyroidism in Adults - UpToDate
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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2022. | This topic last updated: May 20, 2021.
INTRODUCTION
The goal of therapy is restoration of the euthyroid state, which can be readily accomplished in
almost all patients by oral administration of synthetic thyroxine (T4, levothyroxine). Appropriate
treatment reverses all the clinical manifestations of hypothyroidism.
This topic will review the major issues that must be addressed in the treatment of adults with overt
primary hypothyroidism. The treatment of subclinical and central hypothyroidism, as well as
hypothyroidism in children (congenital or acquired), is discussed separately.
APPROACH TO TREATMENT
Our approach described below is largely consistent with the American Thyroid Association (ATA)
Guidelines for the Treatment of Hypothyroidism [1].
Defining hypothyroidism
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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].
● Amelioration of symptoms
● Normalization of serum TSH secretion
● Reduction in the size of goiter (if present)
● Avoidance of overtreatment (iatrogenic thyrotoxicosis)
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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.)
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
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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.
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.
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].
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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].
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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.
● 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
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T4 malabsorption or poor adherence to the medication regimen. (See 'Persistent elevation in TSH'
below.)
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'.)
● Diminished thyroid hormone absorption (patients with impaired acid secretion or other
gastrointestinal disorders [eg, uncontrolled celiac disease]). (See "Diagnosis of celiac disease
in adults".)
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]).
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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.
● 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.
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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".)
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].
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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.)
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
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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.)
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.)
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
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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.)
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 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:
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● 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].
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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'.)
● 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.
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● 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
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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.
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.
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● 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'.)
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'.)
thyroid function when selenium is given to hypothyroid individuals [83]. (See "Postpartum
thyroiditis", section on 'Prevention'.)
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.
Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Hypothyroidism".)
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.)
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● Basics topics (see "Patient education: Hypothyroidism (underactive thyroid) (The Basics)")
● Beyond the Basics topics (see "Patient education: Hypothyroidism (underactive thyroid)
(Beyond the Basics)")
● 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.)
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.)
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● 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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