The Journal of Clinical Endocrinology & Metabolism, 2023, 108, 472–482

https://doi.org/10.1210/clinem/dgac635
Advance access publication 4 November 2022
Approach to the Patient

Approach to the Patient With a Suppressed TSH

Stephanie Smooke Praw1 and Gregory A. Brent1,2

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1
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles,
California 90095, USA
2
Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA
Correspondence: Stephanie S. Praw, MD, Division of Endocrinology, Diabetes, and Metabolism, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave,
CHS 57-145, Los Angeles, CA 90095, USA. Email: ssmooke@mednet.ucla.edu or Gregory A. Brent, MD, Division of Endocrinology, Diabetes, and Metabolism,
David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, CHS 57-145, Los Angeles, CA 90095, USA. Email: gbrent@mednet.ucla.edu.

Abstract
Subclinical hyperthyroidism (SCH) is a laboratory diagnosis defined by a serum thyrotropin (TSH) concentration below the reference range
(< 0.4 mU/L in most assays), and a free thyroxine (FT4) and 3,5,3′-triiodothyronine levels (FT3) in the reference range. Many patients
diagnosed with SCH will be clinically euthyroid while others may present with manifestations characteristic of thyroid hormone excess, such
as tachycardia, tremor, intolerance to heat, bone density loss, or weight loss. In addition to the laboratory abnormalities, patient factors such as
age, symptoms, and underlying heart and bone disease are used to stratify patients for the risk of adverse outcomes and determine the
appropriate treatment. Evaluation should include repeat thyroid function tests to document persistent TSH suppression, investigation of the
underlying cause, as well as evaluation of the patient’s risk of adverse outcomes in the setting of a subnormal TSH. Persistent SCH has been
associated with an increased risk of a range of adverse events, including cardiovascular events such as atrial fibrillation and heart failure, bone
loss and fracture, and in some studies, cognitive decline. Despite the consistent association of these adverse events with SCH, prospective
studies showing improved outcomes with treatment remain limited. Management options include observation without active therapy,
radioactive iodine ablation of the thyroid, antithyroid medication, thyroid surgery, or radiofrequency ablation, as appropriate for the patient and
clinical setting. The choice of therapy should be guided by the underlying etiology of disease, patient factors, and the risks and benefits of each
treatment option.
Key Words: subclinical hyperthyroidism, osteoporosis, atrial fibrillation, thyroid function in elderly, antithyroid drug, radioactive iodine
Abbreviations: ATD, antithyroid drug; ETA, European Thyroid Association; FT3, free 3,5,3′-triiodothyronine; FT4, free thyroxine; HR, hazard ratio; MMI,
methimazole; MMSE, Mini Mental Status Examination; MNG, multinodular goiter; RAI, radioactive iodine; RFA, radiofrequency ablation; SCH, subclinical
hyperthyroidism; T3, 3,5,3′-triiodothyronine; T4, thyroxine; TSH, thyrotropin; TSI, thyroid-stimulating immunoglobulin.

Case reference range in the setting of a decreased serum TSH.

Symptoms or signs of thyroid dysfunction may or may not
A 66-year-old woman with a history of osteoporosis and thyroid
be present. Most guidelines include a grading system to distin­
nodules was referred for evaluation of an abnormal serum thyro­
guish between mild SCH, TSH 0.1 to 0.4 mIU/L, and more
tropin (TSH) of 0.26 mIU/L (reference range, 0.5-4.5 mIU/L)
significant SCH with TSH less than 0.1 mIU/L, and recom­
noted during an evaluation for anemia. The patient was clinically
mend therapy based on the magnitude of TSH suppression
euthyroid. She was not taking any prescribed medications or
(1, 2).
supplements, other than multivitamins. On examination, she
had normal vital signs, no tremor, normal reflexes, and an en­
larged, approximately 60 to 70 g, asymmetric thyroid gland
with a multinodular texture. Bone densitometry results were sig­ Epidemiology
nificant for T score of −3.6 in the lumbar spine (L1-L4), T score
The true prevalence of SCH is difficult to define as there is not
−2.5 in the left femoral neck, and T score −2.0 in the left total
a consensus regarding the need for routine TSH screening. The
hip. Her repeat laboratory evaluation 3 weeks later included a
US Preventive Service Task Force recommends against routine
TSH of 0.18 mIU/L (reference range, 0.3-4.7 mcIU/mL), free
thyroid test screening in nonpregnant, asymptomatic patients
thyroxine (FT4) of 1.3 ng/dL (reference range, 0.80-1.70 ng/dL),
(3). Endocrine societies, such as the American Association of
and free 3,5,3′-triiodothyronine (FT3) of 279 pg/dL (reference
Clinical Endocrinologists, have advocated screening patients
range, 222-383 pg/dL).
who might benefit from treatment of thyroid dysfunction
(4). Those that recommend against routine screening for thy­
roid function typically support their recommendation by the
Definition view that there is limited benefit in treating identified thyroid
Subclinical hyperthyroidism (SCH) is a biochemical diagnosis disease, especially subclinical hypothyroidism, the most com­
characterized by a serum T4 and T3 concentration in the mon underlying abnormality detected with screening (5).

Received: 24 July 2022. Editorial Decision: 25 October 2022. Corrected and Typeset: 18 November 2022
Published by Oxford University Press on behalf of the Endocrine Society 2022.
This work is written by (a) US Government employee(s) and is in the public domain in the US.
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 2 473

A study of a representative population in the United States, Factors influencing thyroid function testing and physio­
without known thyroid dysfunction, reported that 0.7% of logical variations should be considered in the evaluation of a
patients had suppressed TSH (< 0.1 mU/L) and 1.8% of patients low serum TSH. A subnormal TSH may result from substan­
had a TSH level below the reference range (< 0.4 mU/L). Some ces that interfere with the radioimmunoassay. Ingestion of
populations, such as those classified as Black non-Hispanic high doses of biotin can artifactually decrease serum TSH in
Americans, are noted to have lower baseline TSH without evi­ assays using biotin-streptavidin. The presence of heterophile
dence of thyroid disease or presence of thyroid autoantibodies antibodies, human anti-mouse antibodies, and paraproteins
(6). The prevalence of SCH in adult populations also varies are usually associated with a falsely elevated TSH level but
based on age, sex, and iodine intake (7, 8). have rarely been associated with a falsely reduced TSH (10).

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The serum TSH has a diurnal variation with levels in the
morning higher than those in the afternoon and evening, so
Considerations in the Initial Evaluation of the measurement in the morning is recommended (11). In add­
Patient With Suppressed Serum Thyrotropin ition, some TSH suppression is physiologic, such as during
Differentiating the cause of the suppressed TSH is especially fasting (12), in patients with nonthyroidal illness syndrome
important in guiding the extent of diagnostic evaluation and in the setting of critical illness, and in pregnant patients in
treatment. The evaluation of the patient with a suppressed se­ the first trimester, due to human chorionic gonadotropin
rum TSH and an FT4 in the reference range should initially in­ stimulation of thyroid hormone production which results in
clude consideration of factors, other than endogenous chronic decreased TSH production (13). This human chorionic go­
thyroid disease, that may result in a reduced serum TSH meas­ nadotropin effect is more pronounced in patients with hyper­
urement. These include assay interference, physiological con­ emesis gravidarum and in multiple-gestation pregnancies. The
ditions, exogenous factors, and drugs, as well as thyroid majority of these women will have spontaneous correction of
conditions with transient TSH suppression (9) (Table 1). In their abnormal thyroid function tests in the second trimester
addition, a repeat TSH measurement should be performed of pregnancy, and antithyroid drug (ATD) treatment is not
in 6 to 8 weeks, when most, but not all, transient causes of a recommended (13).
suppressed TSH should be normalized. Once it is established When TSH suppression is transient, it may be due to thyroi­
that the suppressed serum TSH persists beyond 6 to 8 weeks, ditis. These conditions include subacute granulomatous (De
an evaluation for underlying chronic thyroid disease, includ­ Quervain) thyroiditis, painless thyroiditis including post­
ing autonomously functioning thyroid nodules, toxic multi­ partum thyroiditis, radiation-induced thyroiditis, or palpa­
nodular goiter (MNG), and Graves disease, should be tion thyroiditis (see Table 1). Rarely, a suppressed TSH can
pursued (discussed later). be associated with an early destructive phase of Hashimoto
thyroiditis that results in the release of stored thyroid hor­
Table 1. Etiologies of subclinical hyperthyroidism mone and a transient thyrotoxicosis.
Exogenous etiologies include overtreatment with thyroid
Endogenous hormone medication with either excessive replacement causing
Multinodular goiter with autonomy iatrogenic hyperthyroidism, intentional suppressive therapy
Hyperfunctioning thyroid nodule for higher-risk thyroid cancers, factitious hyperthyroidism,
Graves disease or use of thyroid hormone for athletic performance enhance­
ment (14). Exogenous levothyroxine-suppressing serum TSH
Exogenous
is usually associated with a reduced serum thyroglobulin con­
Excess levothyroxine supplementation
centration, in contrast to an elevated level with endogenous
Excess desiccated thyroid extract hyperthyroidism. Pituitary and hypothalamic dysfunction (in­
Factitious thyroid hormone ingestion cluding nonthyroidal illness syndrome and nonfunctioning pi­
Transient tuitary adenomas) may be associated with a subnormal serum
Subacute thyroiditis—painless and painful TSH due to underproduction of TSH. Struma ovarii and
Destructive phase of Hashimoto thyroiditis
Radiation thyroiditis
Table 2. Drugs associated with suppressed serum thyrotropin
COVID-19 infection
Drugs (see Table 2) Drugs associated with subacute thyroiditis and triggering Graves
Physiologic/disease conditions with low thyrotropin disease
Fasting Iodine-containing medications and contrast agents
Severe nonthyroidal illness syndrome Amiodarone
Pituitary/hypothalamic disease Immune check point inhibitors
Psychiatric illness Drugs that suppress thyrotropin
First trimester of pregnancy Glucocorticoids
Hyperemesis gravidarum Dopamine
Struma ovarii Bexarotene (retinoid X receptor agonist)
Metastatic follicular thyroid cancer (rare) Dobutamine
Laboratory artifact Bromocriptine
Biotin assay interference Somatostatin analogues
Heterophile antibody assay interference Amphetamines
474 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 2

metastatic follicular thyroid cancer may be associated with Table 3. Evaluation to risk-stratify patient
TSH suppression from excess production of thyroid hormone.
A range of medications are also associated with subnormal Cardiovascular and stroke risk factors
TSH (15) (Table 2), some triggering SCH and others causing dir­ Lipid profile
ect suppression of TSH. Iodine and iodine-containing medica­ EKG
tions, such as amiodarone and iodine contrast agents, and Echocardiography
immune checkpoint inhibitors, can induce hyperthyroidism, Holter monitor or ambulatory cardiac monitor
causing subacute thyroiditis and triggering Graves disease in sus­
Carotid Doppler flow study
ceptible patients. Medications associated with thyroiditis in­

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clude lithium, tyrosine kinase inhibitors, interferon α, and Bone assessment
interleukin-2. Patients exposed to centrally acting medication, Assess dietary calcium intake
such as high-dose glucocorticoids, dopamine, and somatostatin Evaluate for risk factors for “secondary osteoporosis” including
analogues, do not usually require any further treatment and the family history of osteoporosis, hip fracture, glucocorticoid
suppressed TSH normalizes when treatment is discontinued administration, alcohol consumption, tobacco use
(15). Treatment with the retinoid X receptor (RXR) agonist, Bone densitometry
bexarotene, however, produces TSH suppression and reduced Serum/urine measures of calcium
serum FT4 that typically requires thyroxine replacement (16). Serum vitamin D measurement
Patients on amiodarone with overt thyrotoxicosis, but not Serum and urine bone turnover markers
SCH, have an increased risk for major adverse cardiac events Cognitive function assessment
compared to patients with a normal range TSH, so treatment
MMSE
is not recommended for amiodarone-associated SCH (17).
MoCA
Finally, SARS-CoV-2 or COVID-19 infection has been associ­
ated with alteration in thyroid function in multiple observational Abbreviations: EKG, electrocardiogram; MMSE, Mini Mental Status
and retrospective studies. Potential explanations of thyroid func­ Examination; MoCA, Montreal Cognitive Assessment.
tion abnormalities in the setting of COVID-19 infection include
infection causing nonthyroidal illness syndrome, hypothalamic- evaluation as management often involves only observation
pituitary dysfunction, direct thyroid cell destruction by and monitoring of serum TSH.
COVID-19 infection, and immune-mediated effect on the thy­ In patients in whom the suppressed TSH levels persist and
roid by elevated levels of circulating interleukin-6 (18). In add­ treatment is being considered, further evaluation should be
ition, SARS-CoV-2 uses angiotensin-converting enzyme 2 and performed to determine the underlying cause (Table 4).
transmembrane protease serine 2 to infect host cells. Evaluation may include measurement of antithyrotropin recep­
Expression of these molecular complexes is high both in the thy­ tor antibodies or TSI, ultrasound to evaluate for thyroid nod­
roid and the lungs, which may directly contribute to thyroid dys­ ules, thyroid enlargement, or alteration in echotexture,
function in infected individuals (18–20). Patients with thyroid scintigraphy or radioactive iodine uptake to identify
coronavirus infection have also been reported to develop sub­ thyroiditis (very low uptake) or autonomously functioning thy­
acute thyroiditis. COVID-19 infection can also be an immune ac­ roid tissue (increased uptake), or assessment of urinary iodine
tivation trigger for Graves disease, seen approximately 1 month excretion. Patients with a suppressed serum TSH and an ele­
after infections with SARS-CoV-2 (18, 21–25). vated radioactive iodine uptake, which includes patients with
either Graves disease or toxic goiter, are most likely to have per­
sistent hyperthyroidism. The goal of diagnosis in these patients
Clinical Approach/Diagnostic Evaluation of is to assist with appropriately tailoring treatment and prevent­
ing complications of persistent SCH.
Endogenous Hyperthyroidism
The natural history of SCH is variable and the progression to
overt hyperthyroidism occurs in 0.5% to 7.0% of affected pa­ Implications of Subclinical Hyperthyroidism
tients per year and reversion to normal in 5% to 12% of pa­
While the majority of patients with SCH are believed to be
tients per year. Progression is more common in patients with
clinically euthyroid, suppression of TSH has been associated
TSH less than 0.01 mU/L compared to those with a TSH of
0.01 to 0.4 mU/L (2, 26–33). In a small study of 16 patients Table 4. Diagnostic studies for underlying etiology of
with SCH followed for 11 to 36 months, TSH normalized in suppressed thyrotropin
5/7 patients with positive thyroid-stimulating immunoglobu­
lin (TSI) and persisted in the 9 patients with MNG (34). The Thyroid function studies—serum concentration of free T4, T4 by
higher likelihood of persistent SCH in patients with MNG dialysis, T3, free T3, and thyroglobulin
has been corroborated in other studies (8, 32, 33). Thyroid peroxidase antibodies
Determining the cause of subnormal TSH is imperative to TSH R Abs, TSI
guide subsequent patient management. Diagnostic evaluation Spot or 24-h urine iodine measurement
for patients with SCH should be dictated by risk stratification
Thyroid ultrasound
of the patient for complications of SCH (Table 3). Patients
Doppler flow studies
older than 65 years, those with history of cardiovascular dis­
ease or bone loss, or those with TSH less than 0.1 mU/L, merit Radioiodine uptake and scan
further investigation to guide treatment. Younger patients
Abbreviations: T3, 3,5,3′-triiodothyronine; T4, thyroxine; TSH R Ab,
without risk for complications, whose TSH is greater than TSH receptor antibodies; TSH, thyrotropin; TSI, thyroid-stimulating
0.1 to the lower limit of normal, may not require further immunoglobulin.
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 2 475

in multiple studies with an effect on mortality, cardiovascu­ Quality of Life, Cognitive Function, and
lar health, bone density, and possibly cognitive function. Dementia
These potential complications will be explored in detail
next. Patients are also at risk of progression to overt hyper­ Patients with SCH can experience palpitations, heat intoler­
thyroidism. While patients with mild SCH frequently have a ance, and anxiety. As a result, the quality of life in patients
reference range TSH on follow-up evaluation, those with with SCH has been investigated in a myriad of studies includ­
TSH less than 0.1 mIU/L are more likely to have persistent ing in patients both with endogenous and exogenous hyper­
disease or progression to overt hyperthyroidism. The best thyroidism as well as in patients with SCH of varying
predictor of progression has been shown to be the baseline duration. These studies have employed various tools including

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TSH level (33, 35), but it is also recognized that patients questionnaires, such as the Short Form-36, which assess gen­
with nodular thyroid disease are more likely to develop overt eral well-being during the 30 preceding days; the
hyperthyroidism in response to a trigger, such as following a Multidimensional Fatigue Inventory (MFI-20), which assesses
large iodine load (36). fatigue; the Hospital Anxiety and Depression Scale; and the
Multiple studies have demonstrated an increase in mortality Symptom Rating Scale, which was developed to assess symp­
associated with hyperthyroidism (37–41). The duration toms associated with thyroid hormone excess. Review of mul­
of TSH suppression has been associated with mortality tiple studies of patients with endogenous SCH, quality of life,
(42, 43). A recent study by Lillevang-Johansen et al (44) inves­ and symptoms differed between the euthyroid and SCH
tigated the effect of treatment of hyperthyroidism on mortal­ groups (55–58). In additional studies of patients with exogen­
ity. They found that the hazard ratio (HR) for mortality was ous SCH, one study showed abnormal symptom rating scores
increased in untreated vs treated hyperthyroid patients and another study demonstrated impaired scores for emotion­
(1.23; 95% CI, 1.12-1.37; P = .001). In patients with SCH al, social, mental, and general health (59, 60). It can be in­
who received treatment, there was a statistically significant ferred from these studies that there are differences in quality
increased mortality when compared with euthyroid controls of life associated with SCH. Yet, none of these studies identi­
(HR, 1.95; 95% CI, 1.48-2.58; P= .001). But, when the fied the duration of hyperthyroidism or differentiated between
data were adjusted for age, sex, and comorbidities, the mortal­ underlying medical causes of SCH. One additional study eval­
ity in the treated group was not significantly different from the uated patients with exogenous SCH in patients with differen­
control population. The HR for mortality in the untreated in­ tiated thyroid carcinoma on TSH-suppressive doses of
dividuals remained higher than in controls (HR, 1.36; 95% levothyroxine for greater than 10 years and evaluated a subset
CI, 1.16-1.60; P = .001). As such, the increased risk of mortal­ of these patients whose levothyroxine dose was titrated to
ity should be taken into account when considering treatment normalize the serum TSH for 6 months. The authors found
of a patient with a suppressed TSH. that the quality of life in patients with SCH was preserved,
It is established that in the patient with cardiovascular dis­ not different from controls, and that restoration of euthyroid
ease, severe SCH (TSH < 0.1 mIU/L) is associated with in­ state after long-term TSH suppression had no additional effect
creased risk of sinus tachycardia, premature atrial and on quality of life (61).
ventricular beats, and diastolic dysfunction. Analysis of a co­ While overt hypothyroidism and hyperthyroidism have
hort of individuals from the Framingham database not on ex­ been identified as causes of cognitive impairment, data on
ogenous thyroid hormone, older than 60 years with low serum the association between SCH and cognitive dysfunction are
TSH, less than 0.1 mU/L (but not 0.1-0.4 mU/L), demon­ less clear (62). Experimentally induced SCH by levothyroxine
strated an increased risk of atrial fibrillation of 32% over supplementation dose in hypothyroidism resulted in slightly
10 years, as compared with 8% in those patients with a nor­ worse Short Form-36 physical component summary and gen­
mal TSH (45). Results were similar in the Cardiovascular eral health subscale, but improved measurements of mood,
Health Study, in which patients older than 65 with SCH compared to the same patients on lower levothyroxine doses
(with both undetectable and subnormal TSH) were found to with a reference range TSH (63). A recent meta-analysis by
have a significant excess of atrial fibrillation over 13 years Rieben et al (64) evaluated 11 prospective cohorts and found
(46). Despite the risks of dysrhythmia, several studies have that SCH, but not hypothyroidism, may be associated with an
concluded that mild thyroid hormone excess was not associ­ elevated risk for dementia. However, decline in the Mini
ated with an increase in coronary heart disease (47, 48). Mental Status Examination (MMSE), a surrogate for cogni­
In the patient with low bone density, especially in postme­ tive decline, was minimal for patients with both subclinical
nopausal women not treated with estrogen replacement ther­ hypothyroidism and SCH. An individual participant data ana­
apy, the risk of osteoporotic fracture is increased in patients lysis of 23 cohorts from Europe, North America, Australia,
with severe endogenous hyperthyroidism and even in some and Asia, that included almost 75 000 participants, found
patients with milder TSH suppression. Exogenous SCH in no association of cognitive decline, as reflected primarily in
patients with TSH less than 0.03 mIU/L has also been associ­ the MMSE, and SCH or hypothyroidism (65).
ated with increased risk of hip, but not vertebral, fracture in
some studies (49–52). The increased fracture risk has been
postulated to be associated with the direct effect of thyroid Treatment Options
hormone on bone metabolism and the acceleration of bone The approach to treatment of SCH depends on patient sex, age,
turnover and bone loss as determined by biochemical magnitude of TSH suppression, and risk stratification (see
markers of increased bone resorption—increased urinary Fig. 1). Guidelines from the American Thyroid Association
pyridinoline and deoxypyridinoline excretion, and increased and American Association of Clinical Endocrinologists recom­
urinary hydroxyproline excretion (53, 54). Whether treat­ mend treatment for patients with TSH less than 0.1 mIU/L in
ment of SCH reverses damage to the bone and restores the setting of age greater than or equal to 65 years with cardiac
bone mass is less clear. risk factors, heart disease, or osteoporosis, postmenopausal
476 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 2

Paent with persistent serum TSH below reference

range, T4 and T3 in reference range

Evaluate Eology: Serum TSH-R Ab or TSI, Thyroid

Ultrasound, 24 hr RAI Uptake and Scan

Risk Strafy (as indicated clinically): cardiac disease: EKG, echocardiogram,

ambulatory heart rhythm monitor, bone status: postmenopausal woman,
history of Fx, vitamin D level, bone density measurement

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Younger Age, Serum Younger Age, Serum Age >65, Serum TSH
Age >65, Serum TSH
TSH 0.1-0.4 mU/L TSH <0.1 mU/L 0.1-0.4 mU/L
<0.1 mU/L
Risk factors for cardiac
disease or bone loss, or
acve thyroid diseases
No acve cardiac or bone Acve cardiac No Yes
disease or bone
disease
Treatment of underlying
thyroid disease
Observaon, TFTs every 6-12 months.
If symptomac, treat with ATDs and beta Autonomous nodule or goiter
Graves disease
blockers as needed Treat with ATDs, RAI, surgery or
Treat with ATDs, RAI, or surgery
RFA

Figure 1. Algorithm for the approach to a patient with a persistent serum TSH concentration below the reference range and a reference range serum
free T4 and free T3 concentration. ATD, antithyroid drug; EKG, electrocardiogram; Fx, fracture; RAI, radioiactive iodine; RFA, radiofrequency ablation
TSH, thyrotropin; T4, thyroxine; T3, 3,5,3′-triiodothyronine; TSH-R Ab, TSH receptor antibody; TSI, TSH receptor stimulating immunoglobulin.

women who are not taking estrogens or bisphosphonates, and Antithyroid medications are generally safe for achieving eu­
individuals with symptoms of hyperthyroidism. Treatment can thyroid state, although they carry the rare but well-established
also be considered in patients younger than 65 years with per­ risks of agranulocytosis and hepatotoxicity. A recent system­
sistent TSH levels less than 0.1 mIU/L. The European Thyroid atic review evaluated 1660 patients with duration of treat­
Association (ETA) guidelines also provide a strong recommen­ ment ranging between 2.1 and 14.2 years (mean duration,
dation for treatment of patients older than 65 with TSH be­ 5.8 years or 10 000 patient-years). Major complications oc­
tween 0.1 and 0.39 mIU/L with cardiovascular disease or curred in only 14 patients (7 with severe agranulocytosis, 5
comorbidities including peripheral arterial disease, stroke, dia­ with severe liver damage, 1 antineutrophil cytoplasmic auto­
betes, or renal failure (66). The ETA recommends individual­ antibody [ANCA]-associated glomerulonephritis, 1 vascu­
ized consideration of treatment in patients younger than litis) (73). More recent studies have demonstrated the safety
65 years, taking in to consideration symptoms and comorbid­ and efficacy of longer-term treatment. In a study of children
ities. Finally, the ETA recommends monitoring of younger, and adolescents, 80% of the adverse events developed within
asymptomatic patients. 3 months of treatment initiation (74). In other studies of adult
The goal of therapy should be to normalize TSH and minimize populations, adverse effects largely occurred within the first 3
the adverse effects of SCH on health, especially focusing on car­ to 6 months of treatment and were associated with higher
diac and bone health. Yet, data from randomized trials are insuf­ doses of antithyroid medication (75, 76). Azizi et al (77) dem­
ficient to provide guidance regarding mitigation of adverse onstrated safety in a cohort of 85 patients with relapse after an
outcomes in patients with untreated vs treated SCH (Table 5). 18-month course of methimazole (MMI) who were subse­
For example, no randomized controlled trials have demon­ quently treated with 10 years of MMI treatment without ser­
strated decreased risk of atrial fibrillation or mortality with treat­ ious complications. This was corroborated in a study of 384
ment of SCH. Some studies have demonstrated improvement in patients treated for 33 months with a maintenance dose of
bone density in postmenopausal women and correction of re­ 2.5 to 5 mg/day of MMI in whom no significant adverse ef­
versible cardiac effects with treatment of SCH (55, 67–70). fects, other than urticaria, were observed. These data regard­
The treatment modalities and strategies for SCH are similar ing the decreased risk of severe adverse events over time, along
to those for overt hyperthyroidism, including antithyroid with additional studies demonstrating the long-term safety of
medication, radioactive iodine ablation (RAI), surgery, and MMI therapy, support long-term use of MMI.
radiofrequency ablation (RFA) of hyperfunctioning nodules One of the most significant drawbacks of MMI therapy has
(Table 6). β-Blockers decrease the adrenergic-sensitizing man­ been the risk of rebound or persistent hyperthyroidism, ran­
ifestations of SCH and may provide benefit in symptomatic ging from 20% to 70% following cessation of treatment.
patients while thyroid hormone production is being reduced Therefore, the ability to safely treat with long-term MMI
and serum TSH is normalized. Given the absence of studies in­ and the ease of an oral medication with daily dosing for
dicating improved outcomes for most of the associated condi­ most, makes it a more acceptable treatment option (78, 79).
tions after treatment to normalize the serum TSH, it is Recent studies have shown that with 6 years of continuous
especially important to consider the risk and benefits of any se­ treatment of patients with Graves disease, the relapse rate de­
lected therapy, as well as individual patient characteristics and creased to 19.1% (80) and another demonstrated only a 15%
goals, in determining appropriate treatment plan. relapse rate after 5 to 10 years of treatment vs 53% in patients
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 2 477

Table 5. Evidence-based indications for treatment of subclinical hyperthyroidism in older adults (aged > 65 y)

Outcome Strength of association Benefit of treatment

TSH TSH <

0.1-0.4 0.1

Progression to overt hypothyroidism Weak Strong Early treatment may prevent complications associated with longer duration of
suppressed TSH
Symptoms of hyperthyroidism Weak Weak Majority of patients with SCH are clinically euthyroid though those who are

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symptomatic may benefit from treatment
Risk of bone loss and major Moderate Strong Uncertain benefit of treatment
osteoporotic fracture
Risk of cardiovascular disease Weak Strong Uncertain benefit of treatment
Risk of atrial fibrillation Strong Strong Uncertain benefit of treatment
Risk of cognitive decline Weak Weak Uncertain benefit of treatment
QoL Moderate Moderate Single study found no effect of treatment to normalize TSH on QoL
Mortality Weak Moderate Limited data demonstrate increased mortality in untreated vs treated patients

Abbreviations: QoL, quality of life; SCH, subclinical hyperthyroidism; TSH, thyrotropin.

Table 6. Treatments for sustained endogenous subclinical hyperthyroidism

ATD RAI Surgery RFA

Indication Graves disease, MNG, Graves disease, MNG, Graves disease, MNG, Hyperfunctioning nodule
hyperfunctioning hyperfunctioning nodule hyperfunctioning nodule
nodule
Usual First-line therapy for First or second line (after Used in MNG if thyroid is large Usually in patients with
recommendation most patients who ATDs) for MNG or with signs of airway narrowing hyperfunctioning nodule
meet criteria for hyperfunctioning nodule. or tracheal deviation or who are not candidates or
treatment May be used if suspicion of cancer, alternative refuse RAI or surgery, but
complications of long-term to RAI, potential to preserve indications are expanding
ATD use or patient remaining thyroid gland with greater experience
preference function
Usual treatment Methimazole, usual Single dose of RAI, I131, Extent of surgery dictated by FNA before treatment, if
approach starting dose 5-10 mg/d adjusted based on 24-h goiter/nodule size and location appropriate. No. of
uptake and gland size, treatments needed depends
higher doses often needed on size and volume of
for larger MNG and for nodules
autonomous nodules
Efficacy Normalization of TSH Single dose of RAI effective in Uniform high rate of success to Efficacy varies depending on
achieved in essentially ∼80%-0% of patients achieve euthyroidism size and volume of nodule
all patients that
tolerate therapy
Time to respond to Normalization of TSH Normalization of TSH usually Autonomous thyroid hormone Normalization of TSH within
therapy typically 4-12 wk, seen in 6-8 wk production reversed 1 y in ∼50% of patients (71).
depending on immediately, thyroid test Other studies report 86% in
magnitude and normalization dictated by nodules < 1.2 cm and 42%
duration of half-life of serum T4 (7-10 d) in nodules > 1.2 cm (72)
suppression and TSH “recovery” of 4-6 wk
Complications/side Rash, liver inflammation, Small malignancy risk Rare hypoparathyroidism (if Rare hematoma, skin burn,
effects agranulocytosis very hypothyroidism risk, total thyroidectomy) and voice change, brachial
rare greatest with Graves and recurrent laryngeal nerve plexus injury,
MNG, less with damage hypothyroidism, or
autonomous nodule thyroiditis

Abbreviations: ATD, antithyroid drug; FNA, fine-needle aspiration; MNG, multinodular goiter; RAI, radioactive iodine treatment; RFA, radiofrequency
ablation; SCH, subclinical hyperthyroidism; T4, thyroxine; TSH, thyrotropin.

treated for 18 months (81). These studies confirm the efficacy RAI was traditionally used in the United States as first-line
of longer-term MMI treatment to secure more durable remis­ therapy for autonomously functioning thyroid nodules and
sion in patients with Graves disease. Patients with toxic MNG hyperthyroidism associated with Graves disease, but is used
are unlikely to achieve remission with antithyroid medication, much less in Europe and Asia (83). There has, however,
although long-term therapy of toxic goiter with MMI is effect­ been a steady reduction in the use of RAI for hyperthyroidism,
ive and safe (82). including in the United States (84, 85). Radioactive iodine
478 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 2

show inconsistent outcomes. In a study using the Clalit

Health Services database by Gronich et al (87), there was no
association found between radioactive iodine treatment and
solid tumor malignancy. This conclusion was in keeping
with some earlier studies that have not demonstrated an asso­
ciation between RAI for hyperthyroidism and malignancy
(88, 89). A more recent study by Kitahara et al (90) analyzed
the 1998 Cooperative Thyrotoxicosis Therapy Follow-up
Study (CTTFUS) cohort, extended the follow-up time, and ap­

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plied a new dosimetric model for estimating tissue absorbed
doses of radiation. They demonstrated a dose-response associ­
ation between RAI treatment and the risk of cancer death. They
concluded that for every 1000 patients with hyperthyroidism
receiving between 150 and 250 mGy, an estimated excess of
19 (95% CI, 3-40) to 32 (95% CI, 5-66) solid cancer deaths
could occur. A systematic review and meta-analysis including
12 studies and nearly 480 000 patients, by the same group,
found no significant risk of total cancer incidence or mortality
after RAI therapy for hyperthyroidism, with the exception of
thyroid cancer. Further evaluation of dose response by meta-
analysis showed that increases in the RAI dose were associated
with increases in mortality from solid cancer and breast cancer
(91). As a result, despite the fact that the overall pooled cancer
risk was not significant, the linear dose-response association be­
tween RAI treatment and solid cancer was notable.
Overall, the more recent studies suggest the possibility of a
small increased risk of malignancy in hyperthyroid patients
treated with radioactive iodine. The conclusions regarding
cancer mortality are less definitive, demonstrating either a
small or no absolute increased risk. In addition, there are
criticisms of these analyses, the heterogeneity of study popula­
tions, and skepticism surrounding the conclusions regarding
risk of RAI and subsequent malignancy (92). Further study,
including randomized clinical trials, is needed. Regardless,
discussion of these studies has fueled patient concerns about
the cancer risks from the use of radioactive iodine treatment.
In the meantime, counseling patients regarding these issues
may pose challenges for the treating physician (93).
RFA may be considered for the management of autono­
Figure 2. A, Thyroid ultrasound findings: The left lobe of the thyroid is mously functioning thyroid nodules (94). A benign cytologic
enlarged, measuring 7.5 × 1.7 × 2.9 cm. There is a large,
diagnosis must be confirmed for a nonfunctional nodule by
heterogeneous, predominantly solid mass encompassing the entirety
of the left lobe. There are no abnormal calcifications present. The left 2 ultrasound-guided fine-needle aspirations before proceeding
lobe nodule corresponds to the area of uptake seen on the I-123 scan. with ablation (87–90), but is not required for functional nod­
B, Increased vascularity is shown by Doppler flow. C, Nuclear medicine ules (95). The use of RFA in patients who declined RAI and
I-123 uptake scan. Findings: The images demonstrate an enlarged left surgery, or in whom these approaches were contraindicated,
lobe of the thyroid gland with heterogeneous distribution of tracer
activity seen extending inferiorly. The right lobe of the thyroid gland
has been addressed in several studies, but there is not a consen­
appears normal in size with homogenous tracer distribution. sus among professional societies (2, 96–99). RFA for autono­
Percentage uptake at 6 hours, 3.9%; percentage uptake at 24 hours, mously functioning thyroid nodules normalizes thyroid
8.8%. function tests and reduces the nodule volume up to 70% to
80% at 12 months’ follow-up (72, 100, 101). While most
treatments have been recognized for some time to trigger or studies have demonstrated the greatest success in patients
exacerbate Graves ophthalmopathy, although a range of with nodules less than 1.2 cm in diameter, a prospective study
treatments are available to mitigate this effect (2). Concern of 30 patients with mean nodular volume of 3.9 cm demon­
over the malignancy risk associated with RAI, even with the strated that a single RFA session was successful in reducing
lower doses used for Graves disease and autonomously func­ nodule volume by 75% and achieving euthyroidism at
tioning thyroid nodules, may play a role in the trend toward 12 months in 50% of patients (71).
reduced utilization of this treatment modality and has been Patients undergoing RFA for autonomously functioning
a focus of numerous recent studies. A meta-analysis by thyroid nodules have a lower rate of hypothyroidism than
Sawka and colleagues (86) suggested there may be an those undergoing radioactive iodine or surgery, but a less pre­
increased risk of some solid cancers and leukemia with dictable outcome of resolution of SCH. Overall, the procedure
administered doses of RAI in postthyroidectomy thyroid is well tolerated with symptoms of mild pain and local heat
cancer patients, generally higher than the doses of RAI used sensation in approximately 5% of patients and rare incidence
for management of hyperthyroidism. More recent studies of major complications in less than 1% of treated patients,
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 2 479

including hematoma, skin burn, brachial plexus rupture, per­ treatment options include antithyroid medication,
manent voice change, hypothyroidism, or thyroiditis (102– RAI, surgery, or RFA.
106). Successful treatment is defined as attainment of a eu­
thyroid state without ATDs or thyroid hormone replacement
(107). This success from RFA may be more challenging to
achieve in large nodules (> 3.0 cm), for which sustained re­
Financial Support
mission is less likely. In these cases, surgical resection or This work was partially supported by the US Veteran
RAI may be required for definitive treatment (97, 108). Administration Merit Review Award Program (No.
01BX001966 to G.A.B.).

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Return to the Patient and Conclusion Disclosures
Given the finding of asymmetric thyroid enlargement on phys­
The authors have nothing to disclose.
ical examination, a thyroid ultrasound was completed
(Fig. 2A). The left lobe of the thyroid measured 7. 5 × 1.7 ×
2.9 cm and the right lobe 4.0 × 0.8 × 1.1 cm. Confluent nod­ Data Availability
ules replaced the mid to inferior left thyroid lobe, measuring Data sharing is not applicable to this article as no data sets
up to 47 mm. The nodular area was isoechoic with multiple, were generated or analyzed during the present study.
small cystic spaces, and no suspicious calcifications. Doppler
flow determination showed increased blood flow (Fig. 2B).
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