Benefits of Thyrotropin Suppression Versus the Risks of Adverse Effects in Differentiated Thyroid Cancer

Abstract

Background

: Despite clinical practice guidelines for the management of differentiated thyroid cancer (DTC), there are no recommendations on the optimal serum thyrotropin (TSH) concentration to reduce tumor recurrences and improve survival, while ensuring an optimal quality of life with minimal adverse effects. The aim of this review was to provide a risk-adapted management scheme for levothyroxine (L-T4) therapy in patients with DTC. The objective was to establish which patients require complete suppression of serum TSH levels, given their risk of recurrent or metastatic DTC, and how potential adverse effects on the heart and skeleton, induced by subclinical hyperthyroidism, in concert with advanced age and comorbidities, may influence the degree of TSH suppression.

Summary:

A risk-stratified approach to predict the rate of recurrence and death from thyroid cancer was based on the recently revised American Thyroid Association guidelines. A stratified approach to predict the risk from the adverse effects of L-T4 was devised, taking into account the age of the patient, as well as the presence of preexisting cardiovascular and skeletal risk factors that might predispose to the development of long-term adverse cardiovascular or skeletal outcomes, particularly increased heart rate and left ventricular mass, atrial fibrillation, and osteoporosis. Nine potential patient categories can be defined, with differing TSH targets for both initial and long-term L-T4 therapy.

Conclusion:

Before deciding on the degree of TSH suppression during initial and long-term L-T4 treatment in patients with DTC, it is necessary to consider the aggressiveness of DTC, as well as the potential for adverse effects induced by iatrogenic subclinical hyperthyroidism. More aggressive TSH suppression is indicated in patients with high-risk disease or recurrent tumor, whereas less aggressive TSH suppression is reasonable in low-risk patients. In patients with high-risk DTC and an equally high risk of adverse effects, long-term treatment with L-T4 therapy should be individualized and balanced against the potential for adverse effects. In patients with an intermediate risk for thyroid cancer recurrence and a high risk of adverse effects of therapy, the degree of TSH suppression should be reevaluated during the follow-up period. Normalization of serum TSH is advisable for long-term treatment of disease-free elderly patients with DTC and significant comorbidities.

Introduction

T hyroid cancer is the most frequent endocrine cancer (1), occurring in about 5–10% of patients with a thyroid nodule. The incidence of differentiated thyroid cancer (DTC) has increased by over 4% each decade in the last 30 years (1 –7). The advent of diagnostic procedures such as ultrasonography and ultrasound-guided fine-needle aspiration biopsy is probably the most likely reason for the increase in the detection rate of DTC (8 –10), although the increased incidence across all tumor sizes suggests that other factors may also play a role (11 –15).

Total thyroidectomy and ablation by iodine-131 followed by long-term levothyroxine (L-T4) suppression of thyrotropin (TSH) is the traditional treatment for DTC (2,3,16 –18). The rationale for TSH suppression in DTC stems from experimental and clinical data showing that TSH stimulates thyroid cell proliferation, radioiodine uptake, and thyroglobulin (Tg) production (19 –27). Thyroid hormone treatment reduces serum TSH levels, thereby inhibiting the growth of residual neoplastic tissue (2,3,16 –18,22,28). In patients affected by DTC, TSH suppression with L-T4 can induce the regression of tumor recurrences (29 –31), and endogenous or exogenous increases in TSH may occasionally induce clinical progression of thyroid cancer (32,33). On the other hand, doses of L-T4 that reduce circulating TSH to 0.4 mU/L are able to induce maximum suppression of serum Tg (34), suggesting that increasing the degree of TSH suppression may not further decrease tumor function (35). Further, TSH suppression does not inhibit TSH-independent tumor growth in advanced and metastatic thyroid cancer (16).

The concept of TSH-suppression therapy has changed in recent years because (a) DTC patients generally have an excellent survival rate because of the increasing prevalence of small papillary thyroid cancers (36,37), (b) the sensitivity of TSH assays has improved tremendously, which means that TSH suppression can now be customized (38,39), and (c) TSH suppression, even with normal serum free T4 (FT4) and T3 levels, defines exogenous subclinical hyperthyroidism (SHyper) that may adversely affect the skeletal and cardiovascular systems, especially in the elderly (38,39).

However, despite clinical practice guidelines dealing with TSH suppression in patients with DTC (2,3,17,18,40 –42), there is still no consensus about the serum TSH concentration below the lower limit of the normal range (<0.1 or 0.1–0.4 mU/L) that is required for optimal treatment of patients with thyroid cancer. Also, no recommendations take into account patient age and possible underlying comorbidities, and no recommendations or guidelines determine the balance between the benefit of L-T4 suppressive treatment and the risk of adverse effects of iatrogenic hyperthyroidism.

In this review, we address the following issues: (a) identification of specific groups of thyroid cancer patients with a high risk of recurrence and mortality, (b) the impact of TSH suppression on DTC outcome, (c) identification of adverse effects of exogenous SHyper and identification of specific groups of patients at high risk for adverse effects of exogenous SHyper, and (d) the optimal degree of TSH suppression during early and long-term treatment with L-T4 for DTC. Finally, we propose an algorithm for L-T4 therapy in DTC patients to help physicians select the appropriate degree of TSH suppression, taking into account patient's age and comorbidities.

Identification of Specific Groups of DTC Patients with Varying Risks of Recurrence and Mortality

After initial surgery and remnant ablation, the risk for recurrence and mortality in patients with DTC can be divided into three levels: low, intermediate, and high, according to the American Thyroid Association (ATA) guidelines (2).

The risk is low if the following conditions are fulfilled:

No local or distant metastatic disease;

Complete removal of the macroscopic tumor;

No tumor invasion of locoregional structures or vascular invasion;

The tumor does not have aggressive histology (e.g., tall cell, insular, columnar cell carcinoma); if radioiodine is given, there is no uptake outside the thyroid bed after the first posttreatment whole-body radioiodine scan.

The risk is intermediate if any of the following conditions are present:

Microscopic invasion of the tumor in the perithyroid soft tissues;

The tumor has aggressive histology or there is vascular invasion.

The risk is high if any of the following conditions are true:

Macroscopic tumor invasion;

Incomplete tumor resection;

Distant metastases;

Radioiodine uptake outside the thyroid bed after a posttreatment radioiodine scan performed after ablation of remnant thyroid.

Disease status should be reassessed at 6–12 months after total or near total thyroidectomy and thyroid remnant ablation. Disease-free status comprises all of the following conditions:

No clinical evidence of tumor;

No imaging evidence of tumor (no uptake outside the thyroid bed on the initial posttreatment whole-body scan, or if uptake outside the thyroid bed had been present, no imaging evidence of tumor on a recent diagnostic scan and neck ultrasound);

Undetectable serum Tg levels during TSH suppression and TSH stimulation in the absence of interfering antibodies.

Clinical practice guidelines for the management of thyroid cancer (2,3,17,18,40 –42) recommend undetectable serum TSH levels in high-risk patients at the time of their initial management. As shown in Figure 1, in high-risk patients who have persistent disease, the ATA and European Thyroid Association (ETA) recommend that the serum TSH level be maintained at <0.1 mU/L. In higher-risk but now disease-free patients, the ATA recommends TSH levels between 0.1 and 0.5 mU/L for 5–10 years, whereas the ETA recommends TSH levels be maintained <0.1 mU/L for 3–5 years. In low-risk patients, the initial serum TSH levels should be between 0.1 and 0.5 mU/L in the ATA guidelines and <0.1 mU/L in the ETA guidelines. In low-risk patients who are shown to be disease-free on follow-up testing, both groups recommend that serum TSH be kept in the low normal range.

FIG. 1.

Differences among consensus guidelines of the ATA and ETA for L-T4 therapy in patients with differentiated thyroid cancer. ETA, European Thyroid Association; ATA, American Thyroid Association; TSH, thyrotropin.

Impact of TSH Suppression on DTC Outcome

The optimal concentration of TSH needed to reduce tumor recurrences and improve survival while ensuring a good quality of life with minimal adverse effects is much debated (43 –49). In several studies, fewer cancer recurrences and thyroid carcinoma-related deaths occurred in patients treated with TSH-suppressive L-T4 dosages than in patients who did not receive TSH-suppressive doses of L-T4 (43 –45). A retrospective analysis of a 30-year follow-up in 1322 patients without distant metastases showed that patients treated with L-T4 had 25% fewer recurrences (30% vs. 40%, p < 0.001) and 50% fewer cancer-related deaths (6% vs. 12%) than those who did not receive L-T4 therapy and who had serum TSH levels within the hypothyroid range (43). However, the initial therapy in terms of the extent of surgery and radioiodine ablation was not uniform in the population studied.

Another retrospective study confirmed the survival benefit of a high level of TSH suppression (ranging from 0.05 to 0.1 mU/L) in 141 patients with DTC who were all treated by total thyroidectomy and thyroid remnant ablation, and underwent thyroid hormone treatment after surgery (44). This study was the first to suggest that patients with a greater degree of constant TSH suppression (≤0.1 mU/L) had a trend toward a longer relapse-free survival (p < 0.01) than patients with nonsuppressed TSH (≥1 mU/L); this effect was independent of the initial disease stage. A meta-analysis that included 10 studies examining the effects of TSH suppression in DTC outcomes (46) showed an overall benefit of TSH suppression (relative risk of an adverse event: 0.73, p < 0.05). However, the studies included in this meta-analysis had several drawbacks: possible selection bias, the use of thyroid hormone therapy as a surrogate for total thyroidectomy, differences in treatment and monitoring (for instance, using serum Tg to detect recurrence in more recent studies), and finally, many studies did not distinguish between thyroid hormone replacement therapy and suppression therapy.

The first study on this topic from the National Thyroid Cancer Treatment Cooperative Study Group (NTCCSG) Registry was published in 1998 (47); this study demonstrated that suppression to a very low TSH level reduced recurrence in Stage 3 and 4 patients, but was not beneficial in low-risk patients. However, in multivariate analysis, the effect of TSH suppression in high-risk patients was no longer significant when radioiodine therapy was included in the model. The relationship between long-term TSH suppressive therapy and patient outcome was evaluated in a second prospective study from the NTCCSG Registry of 2936 patients affected by DTC (48). TSH suppression improved overall survival in Stage 2 patients who maintained subnormal serum TSH levels versus those with normal or elevated serum TSH levels, whereas in Stage 3 and 4 patients, overall survival and disease-specific survival were improved in patients who maintained subnormal to undetectable serum TSH levels. Most recently, a Dutch retrospective study assessed recurrence risk in 366 patients with DTC, all treated with total thyroidectomy and radioiodine ablation (49). In individual patients, the percent of serum TSH values of >4.5 mU/L was an independent predictor of death. Further, serum TSH levels of >2 mU/L were also associated with thyroid cancer-specific death and recurrence, whereas there were no differences in deaths or recurrences in patients who maintained serum TSH levels between 0.1 and 0.4 mU/L.

The results of these studies suggest that more aggressive TSH suppression with L-T4 is important in patients with high-risk disease or recurrent tumor, whereas less aggressive TSH suppression is reasonable in low-risk patients (47 –49). This provides a rationale to target TSH levels to the lower part of the normal range in low-risk DTC patients, as recommended by the ATA (2) and the European consensus conference (3).

Adverse Effects of Exogenous SHyper

Adverse cardiovascular effects of exogenous SHyper in young and middle-aged patients

Patients affected by DTC treated with doses of L-T4 leading to undetectable serum TSH levels may have symptoms and signs of thyroid hormone excess and resultant poor compliance with L-T4 treatment (44,50 –56). TSH-suppressive doses of L-T4 can impair quality of life as measured by psychological, social, and physical items, particularly when the serum TSH is undetectable (50 –56). Some important cardiovascular risk factors (increased heart rate, increased left ventricular mass, increased mean arterial pressure, and diastolic dysfunction) can develop in young and middle-aged individuals receiving long-term TSH suppression with L-T4 (57 –65). These alterations may be of clinical importance, because the same cardiovascular risk factors associated with long-term TSH suppression may predict an increased risk for cardiac mortality and future cardiovascular events in the general population (66 –68).

A recent study has evaluated cardiovascular morbidity and mortality in middle-aged patients with exogenous SHyper (69) (Table 1). This large population-based study was performed to evaluate fatal and nonfatal cardiovascular endpoints in 17,684 patients (mean age: 61.6 years) who were under thyroid medication. The median follow-up was 4.5 years and TSH measurements were repeated during the follow-up (overall, the median rate of TSH tests per patient was 1.35 per year). The results were adjusted for age, sex, history of previous thyroid condition, history of cardiovascular disease, socioeconomic status, and presence of diabetes. Patients with suppressed serum TSH (≤0.03 mU/L) were at increased risk for cardiovascular morbidity and mortality and dysrhythmias. For all endpoints, there was an increased risk with older age. Patients with a serum TSH below the reference range, but not suppressed (0.04–0.4 mU/L), had no increased risk of cardiovascular disease or dysrhythmias. As thyroid hormone levels were not reported, it is uncertain whether the patients had normal or frankly elevated serum T4 levels. These data indicate that in patients receiving long-term L-T4 therapy, it may be safe to have a low but nonsuppressed TSH concentration.

Table 1.

Association Between Subclinical Hyperthyroidism and Mortality in Middle Aged, Elderly, and Very elderly Subjects: Epidemiological Evidence

Authors	No. of patients (n = )	Sex	TSH (mU/L)	Age (years)	Follow-up (years)	Cardiovascular risk
Flynn et al. (69)^a	n = 17,684; 1070 with exogenous SHyper and suppressed TSH	W/M	≤0.03	61.6	4.5	Increased cardiovascular morbidity and mortality and increased risk of dysrhythmias with serum TSH ≤0.03 mU/L
	3731 with TSH 0.04–0.4 mU/L)	W/M	0.04–0.4	60.8	4.5	This risk was not elevated in those with low TSH (0.04–0.4 mU/L) vs. those with normal serum TSH (0.4 and 4.0 mU/L)
Bauer et al. (79)^b	n = 9449; 12% were thyroid hormone users	W	≤0.5	≥65	12	No significant association between thyroid hormone use and cardiovascular or cancer mortality among women with baseline TSH above or below the normal range
Gussekloo et al. (90)^c	n = 599; 17 with low TSH	W/M	<0.3	85–89	4	Increased cardiac mortality; higher levels of FT₄ were associated with an increased risk of cardiovascular and all cause mortality
Van den Beld et al. (91)^c	44 with endogenous SHyper	W/M	<0.4	73–94	4	Higher FT4 levels within the normal range (independent of TSH) were associated with a higher risk of mortality

Data reported as mean ± standard deviation.

Data reported in middle-aged patients.

Data reported in elderly patients.

Data reported in very elderly patients.

FT4, free thyroxine.

Adverse cardiovascular effects of exogenous SHyper in older patients

The adverse effects of SHyper are closely related to the patient's age (70). Elderly patients have a higher risk of developing adverse effects of TSH suppression, although they can be less symptomatic than younger persons in the presence of thyroid hormone excess (70). Atrial fibrillation (AF) may be the first manifestation of overt hyperthyroidism or SHyper in elderly patients. Two prospective studies reported an increased risk of AF in elderly subjects affected by endogenous (71,72) or exogenous (71) SHyper compared with euthyroid subjects over a 10- (71) and a 13-year follow-up, respectively (72). Moreover, a higher risk of AF has also been associated even with minimal serum TSH suppression (between 0.1 and 0.4 mU/L) in elderly subjects (72). AF is an important risk factor for cardiovascular morbidity and mortality in thyrotoxic patients and in the general population (73 –78).

Only one study (79) has evaluated the mortality among elderly subjects receiving long-term thyroid hormone therapy (Table 1). The mortality among users of thyroid hormone (12% of 9449 community-dwelling white women aged ≥65 years after 15.8 years of thyroid hormone use) was similar to that of nonusers (relative hazard: 1.11, 95% confidence interval: 0.98–1.24, p = 0.09). Neither low (≤0.5 mU/L) nor high (>5 mU/L) TSH levels were significantly associated with excess mortality among older women using thyroid hormone. However, a recent meta-analysis showed that untreated endogenous SHyper is more harmful in patients with comorbidities (80), such as cardiac disease and diabetes mellitus, and in patients recovering from stroke or hip replacement (81 –83). The study also indicated that absolute excess mortality after the diagnosis of SHyper increases in patients over the age of 60 (80). Aging is accompanied by the development of cardiac hypertrophy, interstitial fibrosis, and myocyte loss, which theoretically may further impair cardiovascular performance. Further, in the study by Iervasi et al., SHyper was an independent predictor of cardiac death in patients with preexisting cardiac conditions; the survival rate was significantly lower in patients with SHyper than in euthyroid patients (81).

Cardiovascular Risk of Increased FT4 Values During L-T4 Therapy

It remains to be established whether or not exogenous and endogenous SHyper exert the same effects at the tissue level (38). Although serum T3 levels are higher in patients with endogenous SHyper than in patients with exogenous SHyper (38), serum FT4 concentrations are often elevated in many patients undergoing L-T4 suppressive therapy. In these patients, serum total T3 and free T3 are usually in the middle of their reference ranges, and the T4/T3 ratio is greater than in patients with endogenous SHyper (38). Therefore, an increased T3 concentration during L-T4 therapy is indicative of overt iatrogenic hyperthyroidism, and the combination of serum total or free T3 and serum TSH may be the best parameters for monitoring TSH-suppression therapy in patients with DTC (84).

Significantly higher serum FT4 levels are present after total thyroidectomy in patients receiving L-T4 treatment compared with their prethyroidectomy levels, especially in those with suppressed TSH (85). Higher serum T4 levels are necessary in thyroidectomized patients to obtain serum T3 concentrations similar to those of euthyroid controls, because of the need to compensate for the absence of the 20% fraction of circulating T3 secreted directly by the thyroid (85 –88). Several epidemiological studies support a link between high FT4 levels and adverse cardiovascular effects in elderly subjects (89 –91). In a population-based study of 5860 subjects who were 65 years and older, the median serum FT4 concentration was higher in patients with AF than in subjects without AF (89). Two studies confirmed the adverse prognostic effects of high FT4 values in very elderly subjects (90,91) (Table 1), with an increased cardiovascular mortality in subjects over the age of 85 years who had high FT4 levels during 4 years of follow-up. These results suggest that high FT4 levels should be avoided in elderly patients receiving long-term TSH-suppression therapy, independent of the serum TSH value.

Bone Mineral Density and Fracture Risk in Exogenous SHyper

Overt hyperthyroidism is an important risk factor for osteoporosis and fractures (92,93). In experimental animals, T4 excess causes osteopenia, which is more severe in cortical bone than in trabecular bone (94). Data on the potential role of TSH on bone remodeling are conflicting (95,96). Two recent reviews assessed the effects of TSH suppressive therapy on bone mineral density (BMD) in patients with DTC (97,98); the studies were stratified according to sex and menopausal status and the results suggested that TSH suppression did not affect BMD in men or in premenopausal women, whereas postmenopausal patients were at risk of bone loss.

Three longitudinal studies evaluated changes of BMD and bone turnover in postmenopausal women with DTC on L-T4 therapy (99 –101) but showed conflicting results. Inconsistent results have also been reported from studies of DTC patients with different degrees of TSH suppression during L-T4 therapy (102 –105). In general, it appears that TSH suppression induced by L-T4 therapy accelerates bone turnover, but only in postmenopausal women; however, the degree of serum TSH suppression required to avoid this effect is unknown.

Several studies have evaluated whether SHyper increases the risk of fractures (69,106,107). Women with a history of thyroid cancer appeared to have their first fracture earlier (p < 0.01) than women without thyroid disease (106). Bauer et al. (107) prospectively evaluated fracture risk in 686 women older than 65 years with low serum TSH due to both exogenous and endogenous SHyper. After adjustment for age, history of hyperthyroidism, and use of estrogen and thyroid hormone, women with a serum TSH level of ≤0.1 mU/L had a threefold increased risk of hip fracture and a fourfold increased risk of vertebral fracture compared with women with normal serum TSH levels. Women receiving L-T4 doses to maintain serum TSH in the range of 0.1–0.5 mU/L also had an increased risk of fractures.

A suppressed serum TSH (≤0.03 mU/L) was associated with a doubled risk of osteoporotic fracture in postmenopausal women (mean age: 60.3 years) in a recent population-based study of all patients taking LT4 therapy (69). Patients with a serum TSH below the reference range, but not fully suppressed (0.04–0.4 mU/L), had no increased risk of fractures. However, data on FT4 levels or T3 levels were not reported in these studies (69,107).

L-T4 Therapy in DTC: A Balance Between Cancer Aggressiveness and the Risk of Adverse Effects

At least 10% of patients with DTC will have a recurrence, and a small number will even succumb to their disease. However, low-risk patients, who make up 80% of all thyroid cancer patients, have a far lower risk of death and will derive little or no benefit from maintaining suppressed serum TSH levels. The key question for clinicians is which patients require total suppression of serum TSH levels, given the risk of recurrent or metastatic DTC, and how do advanced age and comorbidities influence the degree of TSH suppression? As noted earlier, the ATA guidelines allow physicians to assess the aggressiveness of thyroid cancer, defining low-, intermediate-, and high-risk patients with DTC after initial treatment (2).

A similar assessment of the risk of adverse effects of thyroxine suppressive therapy could be formulated based on the risk factors reported in the literature, which are summarized in the following paragraphs (Table 2).

Table 2.

Risk Assessment for Thyrotropin Suppression in Differentiated Thyroid Cancer at Initial Evaluation

Low risk from tumor recurrence or death

• No local or distant metastases

• Complete surgery

• No locoregional or vascular invasion

• No aggressive histology (e.g., tall cell, insular, columnar cell carcinoma)

• No uptake outside the thyroid bed on initial posttreatment scan

Low risk from TSH suppression

• Young and middle-aged patients

• Asymptomatic patients

• No cardiovascular disease

• No alterations of cardiac rhythm

• No symptoms of adrenergic overactivity

• No cardiovascular risk factors

• No comorbidities

• Premenopausal women

• Normal BMD

• No risk factors for osteoporosis

Intermediate risk from tumor recurrence or death

• Microscopic invasion into the perithyroidal soft tissues

• Aggressive histology

• Vascular invasion

Intermediate risk from TSH suppression

• Elderly subjects

• Hypertension

• Symptoms and signs of adrenergic overactivity

• Cigarette smoking

• Cardiovascular risk factors and diabetes

• Perimenopausal women

• Osteopenia

• Risk factors for osteoporosis

High risk from tumor recurrence or death

• Increased age (>45–50 years)

• Increased size (>4 cm)

• Macroscopic tumor invasion

• Incomplete tumor resection

• Distant metastases

• Radioiodine uptake outside the thyroid bed after a posttreatment radioiodine scan performed after ablation of remnant thyroid

High risk from TSH suppression

• Clinical heart disease

• Very elderly

• Postmenopausal

• Comorbidities

BMD, bone mineral density.

For example, the risk of adverse effects could be considered high in the following patient groups:

Patients with a history of paroxysmal or persistent atrial fibrillation (71,72,78), especially in the presence of left atrial enlargement (78);

Patients with previous history of stroke or transient ischemic attack (78);

Other comorbidities (e.g., diabetes, renal failure) (80);

Left atrial dilatation (78);

Increased risk factors for stroke (78);

Patients with a history of congestive heart failure (81);

The presence of valvular heart disease (78);

Known or suspected vascular disease (coronary or peripheral arterial disease) (80 –83);

Evidence of osteoporosis or a previous fragility fracture (69,107).

The risk of adverse effects could be considered to be intermediate in the following patient groups:

Otherwise healthy patients older than 60 years, because of the potential risk of AF (71,72);

Hypertension (108);

Increased left ventricular mass or left ventricular hypertrophy (57,59,61,63,64);

Diastolic dysfunction (61 –63);

The presence of thyroxine-related adrenergic signs and symptoms (51,52,54,61);

Cigarette smoking;

The presence of cardiovascular risk factors (38);

Perimenopausal women, because of the potential risk of osteoporosis (97,98);

Osteopenia (38);

Risk factors for osteoporosis (38).

The risk of adverse effects of TSH suppression would be low in the following patient groups:

Young and middle-aged patients;

Asymptomatic patients;

No cardiovascular disease;

No alterations of cardiac rhythm;

No symptoms of adrenergic overactivity;

No cardiovascular risk factors;

No comorbidities;

Premenopausal women;

Normal BMD;

No risk factors for osteoporosis.

The complexity of the treatment decision-making process is illustrated in Tables 3 and 4. There are nine potential conditions:

(a) TSH suppression in patients with metastases or a high risk of tumor progression and a low risk of adverse effects from L-T4

Table 3.

Suggested Initial Thyrotropin Targets in Thyroid Cancer Patients According to Risk Assessment

		Risk of cancer recurrence and progression
		High	Intermediate	Low
Risk from T₄ therapy	High	<0.1 mU/L^a	<0.1 mU/L^a	0.5–1 mU/L
	Intermediate	<0.1 mU/L^b	<0.1 mU/L^b	0.5–1 mU/L
	Low	<0.1 mU/L	<0.1 mU/L	0.1–0.5 mU/L

With high risk from L-T4: consider cardiovascular drugs, calcium, vitamin D, and antiresorptive drugs.

With intermediate risk from L-T4 and high or intermediate risk of tumor progression: consider β-adrenergic blocking drugs, calcium, and vitamin D.

L-T4, levothyroxine.

Table 4.

Suggested Thyrotropin Targets in Thyroid Cancer Patients According to Risk Assessment During Follow-up

		Risk of cancer recurrence and progression
		High	Intermediate	Low
Risk from T₄ therapy	High	<0.1 mU/L persistent or metastatic disease; 0.1–0.5 mU/L if disease free for 5–10 years^a	0.5–1 mU/L if disease free for 5–10 years, then 1–2 mU/L	1–2 mU/L
	Intermediate	<0.1 mU/L persistent or metastatic disease^b; 0.1–0.5 mU/L if disease free for 5–10 years	0.1–0.5 mU/L if disease free for 5–10 years, then 1–2 mU/L	1–2 mU/L
	Low	<0.1 mU/L persistent or metastatic disease^c; 0.1–0.5 mU/L if disease free for 5–10 years	0.1–0.5 mU/L if disease free for 5–10 years, then 0.3–2 mU/L	0.3–2 mU/L

With high risk from L-T4 with persistent/metastatic disease: TSH suppression should be adapted to the clinical situation.

With intermediate risk from L-T4 with persistent/metastatic disease: consider cardiovascular drugs, calcium, and vitamin D.

With low risk from L-T4 with persistent/metastatic disease: periodic cardiovascular and BMD assessment.

In patients with high-risk disease and a low risk of L-T4-related adverse effects, serum TSH should be undetectable (<0.1 mU/L) at initial therapy (Table 3). An undetectable serum TSH should be maintained indefinitely in the presence of persistent or metastatic disease (Table 4). This is consistent with the ATA and ETA guidelines.

(b) TSH suppression in patients with a high risk of tumor progression and a high or intermediate risk of adverse effects from L-T4

TSH suppression is particularly difficult in patients with comorbidities, and elderly patients with DTC are usually at a higher risk for both cancer progression and adverse effects from L-T4 therapy. Here, clinicians must use their best judgment, balancing the risks from thyroid cancer recurrence or spread, with the concomitant risks of atrial fibrillation and fractures. Initial serum TSH suppression to <0.1 mU/L is recommended in patients with high-risk DTC because it may improve mortality (47 –49) (Table 3). However, given the potential risk of adverse effects, the degree of TSH suppression should be reevaluated during follow-up (Table 4). TSH suppressive therapy (TSH <0.1 mU/L) should theoretically be continued in high-risk patients with residual or metastatic thyroid cancer; however, these patients should undergo periodic cardiologic evaluation and bone density assessment, and the degree of TSH suppression should be adapted to the clinical situation. Digoxin, β-blockers, angiotensin-converting enzyme inhibitors, and other cardiovascular drugs may be useful in patients at high risk of adverse cardiovascular events during TSH suppression in the presence of heart failure or left ventricular dysfunction. Treatment with L-T4 and administration of these drugs should be individualized to improve cardiac hemodynamics, to control the ventricular response and prevent thromboembolism in presence of AF, and to reduce the frequency and severity of AF recurrences in presence of paroxysmal AF (109 –112).

Calcium supplementation may prevent bone loss in postmenopausal patients with exogenous SHyper and inadequate calcium intake (113). Moreover, vitamin D, estrogen, and/or bisphosphonates (114,115) may be able to prevent the bone loss induced by suppressive doses of L-T4 in postmenopausal women. However, a recent report has shown that the response to alendronate was incomplete in those women with thyroid cancer who were on suppressive doses of L-T4 for more than 6 or 9 years, compared with women on L-T4 suppression for only 3 years (116). Consequently, calcium, vitamin D, and/or antiresorptive drugs should be considered earlier rather than later, to reduce the risk of osteoporosis in postmenopausal patients.

In symptomatic patients and in subjects with an intermediate risk of adverse effects, β-adrenergic blocking drugs or other cardiovascular drugs may be useful to reduce the increased heart rate and prevent the increase in left ventricular mass (51,61). Calcium and vitamin D can be useful in the presence of osteopenia to prevent further bone loss during TSH suppression (99).

In high-risk patients who are clinically and biochemically free of disease for 5–10 years during follow-up, TSH suppressive therapy should be liberalized to achieve serum TSH levels of 0.1–0.5 mU/L (2,3) (Table 4). During the follow-up, similar to the initial treatment, the TSH target should be adapted to the clinical situation to avoid the negative cardiovascular and skeletal effects that can represent a risk for those patients with high risk of adverse effects. Moreover, given the possible additional adverse effects of an elevated serum FT4 on cardiovascular outcomes (89 –91), it would also be reasonable to maintain the serum FT4 as close to normal as possible, especially in elderly high-risk patients.

(c) TSH suppression in patients at intermediate risk of tumor progression and a low, intermediate, and high risk of adverse effects from L-T4

An undetectable TSH value (<0.1 mU/L) should be maintained in the first years after the diagnosis of thyroid cancer in patients with intermediate risk (Table 3). However, in those patients with an intermediate risk for thyroid cancer and high risk of adverse effects, the degree of TSH suppression should be modified according to the clinical assessment and reevaluated during the follow-up period. After 5–10 years of follow-up, a TSH value between 0.5 and 2 mU/L should be considered, when the stimulated serum Tg is undetectable and there is no clinical and radiological evidence of disease (Table 4).

(d) TSH suppression in patients with a low risk of tumor progression and a low risk of adverse effects

A TSH value between 0.1 and 0.5 mU/L is suggested for initial therapy in patients with a low risk of cancer progression and a low risk of adverse effects (Table 3). After complete remission has been demonstrated, normalization of serum TSH levels is advisable in patients free of disease, with a TSH target within the low normal range (0.3–2 mU/L) (Table 4).

(e) TSH suppression in patients with a low risk of cancer progression and a high and intermediate risk of adverse effects

In patients with a low risk of cancer progression and a high and intermediate risk of adverse effects, a TSH value between 0.5 and 1 mU/L would be reasonable for initial therapy (Table 3). In disease-free low-risk patients during the follow-up, a TSH value of 1–2 mU/L is appropriate in patients at high risk of adverse effects, especially in elderly patients and in patients with underlying heart disease or comorbidities (Table 4).

Conclusions

TSH suppression therapy decreases the rate of recurrences and mortality only in high-risk DTC. The degree to which serum TSH should be suppressed in a given patient depends not only on the potential benefits, but also on the potential risks. The most appropriate management of high-risk patients with residual thyroid cancer who are elderly or who have underlying serious comorbidities (e.g., cardiovascular disease, diabetes, osteoporosis) is uncertain. Elderly patients are at higher risk of both thyroid cancer progression and the adverse effects of TSH suppression. Consequently, the potential benefits of TSH suppression need to be weighed against the potential adverse effects of TSH suppression on the heart and skeleton in these subjects.

In the future, TSH suppression may be achieved with thyroid hormone analogs that suppress pituitary TSH secretion, with less effect on the cardiovascular system and the skeleton, similar to the selective estrogen receptor modulators that have been used with so much success (117). Another possibility is the development of retinoids or other compounds that specifically decrease pituitary TSH secretion (118). Finally, an integrated genetic and morphological approach to the pathological diagnosis of DTC may help to identify those patients with DTC who are at high risk of recurrence and who will most benefit from TSH suppression, and those patients who are at low risk and who do not require it.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

References

Jemal

, Siegel

, Ward

, Hao

, Xu

, Murray

, Thun

. 2008. Cancer Statistics. CA Cancer J Clin, 58:71–96.

Cooper

, Doherty

, Haugen

, Kloos

, Lee

, Mandel

, Mazzaferri

, McIver

, Pacini

, Schlumberger

, Sherman

, Steward

, Tuttle

. 2009. Revised management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 19:1167–1214.

Pacini

, Schlumberger

, Dralle

, Elisei

, Smit

JWA

, Wiersinga

, the European Thyroid Cancer

Taskforce

. 2006. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol, 54:787–803.

Davies

, Welch

. 2006. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA, 295:2164–2167.

Liu

, Semenciw

, Ugnat

, Mao

. 2001. Increasing thyroid cancer incidence in Canada, 1970–1996: time trends and age–period–cohort effects. Br J Cancer, 85:1335–1339.

Leenhardt

, Grosclaude

, Chérié-Challine

. 2004. Increased incidence of thyroid carcinoma in France: a true epidemic or thyroid nodule management effects? Report from the French Thyroid Cancer Committee. Thyroid, 12:1056–1060.

dos Santos Silva

, Swerdlow

. 1993. Thyroid cancer epidemiology in England and Wales: time trends and geographical distribution. Br J Cancer, 67:330–340.

Mihailescu

, Schneider

. 2008. Size, number and distribution of thyroid nodules and their risk of malignancy in radiation-exposed patients who underwent surgery. J Clin Endocrinol Metab, 93:2188–2193.

Frates

, Benson

, Charboneau

, Cibas

, Clark

, Coleman

, Cronan

, Doubilet

, Evans

, Goellner

, Hay

, Hertzberg

, Intenzo

, Jeffrey

, Langer

, Larsen

, Mandel

, Middleton

, Reading

, Sherman

, Tessler

. 2005. Society of Radiologists in Ultrasound. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radiology, 237:794–800.

10.

Morris

, Ragavendra

, Yeh

. 2008. Evidence-based assessment of the role of ultrasonography in the management of benign thyroid nodules. World J Surg, 32:1253–1263.

11.

Frasca

, Nucera

, Pellegriti

, Gangemi

, Attard

, Stella

, Loda

, Vella

, Giordano

, Trimarchi

, Mazzon

, Belfiore

, Vigneri

. 2008. BRAF (V600E) mutation and the biology of papillary thyroid cancer. Endocr-Relat Cancer, 15:191–205.

12.

Pettersson

, Coleman

, Ron

, Adami

. 1996. Iodine supplementation in Sweden and regional trends in thyroid cancer incidence by histopathologic type. Int J Cancer, 65:13–19.

13.

Chen

, Jemal

, Ward

. 2009. Increasing incidence of differentiated thyroid cancer in the United States, 1988–2005. Cancer, 115:3801–3807.

14.

Rego-Iraeta

, Pérez-Méndez

, Mantinan

, Garcia-Mayor

. 2009. Time trends for thyroid cancer in northwestern Spain: true rise in the incidence of micro and larger forms of papillary thyroid carcinoma. Thyroid, 19:333–340.

15.

Enewold

, Zhu

, Ron

, Marrogi

, Stojadinovic

, Peoples

, Devesa

. 2009. Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980–2005. Cancer Epidemiol Biomarkers Prev, 18:784–791.

16.

Biondi

, Filetti

, Schlumberger

. 2005. Thyroid-hormone therapy and thyroid cancer: a reassessment. Nat Clin Pract Endocrinol Metab, 1:32–40.

17.

Sundram

, Robinson

, Kung

, Lim-Abrahan

, Bay

, Chuan

, Chung

, Huang

, Hsu

, Kamaruddin

, Cheah

, Kim

, Koong

, Lin

, Mangklabruks

, Paz-Pacheco

, Rauff

, Ladenson

. 2006. Well-differentiated epithelial thyroid cancer management in the Asia Pacific region: a report and clinical practice guideline. Thyroid, 16:461–469.

18.

Pitoia

, Ward

, Wohllk

, Friguglietti

, Tomimori

, Gauna

, Camargo

, Vaisman

, Harach

, Munizaga

, Corigliano

, Pretell

, Niepomniszcze

. 2009. Recommendations of the Latin American Thyroid Society on diagnosis and management of differentiated thyroid cancer. Arq Bras Endocrinol Metab, 53:884–97.

19.

Pötter

, Horn

, Scheumann

, Dralle

, Costagliola

, Ludgate

, Vassart

, Dumont

, Brabant

. 1994. Western blot analysis of thyrotropin receptor expression in human thyroid tumors and correlation with TSH-binding. Biochem Biophys Res Commun, 205:361–367.

20.

Lacroix

, Pourcher

, Magnon

, Bellon

, Talbot

, Intaraphairot

, Caillou

, Schlumberger

, Bidart

. 2004. Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters. J Clin Endocrinol Metab, 89:1423–1428.

21.

Durante

, Puxeddu

, Ferretti

, Morisi

, Moretti

, Bruno

, Barbi

, Avenia

, Scipioni

, Verrienti

, Tosi

, Cavaliere

, Gulino

, Filetti

, Russo

. 2007. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J Clin Endocrinol Metab, 92:2840–2843.

22.

Brabant

. 2008. Thyrotropin suppressive therapy in thyroid carcinoma: what are the targets? J Clin Endocrinol Metab, 93:1167–1169.

23.

Spencer

, LoPresti

, Fatemi

, Nicoloff

. 1999. Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement. Thyroid, 9:435–441.

24.

Pacini

, Lari

, Mazzeo

, Grasso

, Taddei

, Pinchera

. 1985. Diagnostic value of a single serum thyroglobulin determination on and off thyroid suppressive therapy in the follow-up of patients with differentiated thyroid cancer. Clin Endocrinol (Oxf ), 23:405–411.

25.

Heemstra

, Liu

, Stokkel

, Kievit

, Corssmit

, Pereira

, Romijn

, Smit

. 2007. Serum thyroglobulin concentrations predict disease-free remission and death in differentiated thyroid carcinoma. Clin Endocrinol (Oxf ), 66:58–64.

26.

Dulgeroff

, Hershman

. 1994. Medical therapy for differentiated thyroid carcinoma. Endocr Rev, 15:500–515.

27.

Ichikawa

, Saito

, Abe

, Homma

, Muraki

. 1976. Presence of TSH receptor in thyroid neoplasms. J Clin Endocrinol Metab, 42:395–398.

28.

Carayon

, Thomas-Morvan

, Castanas

, Tubiana

. 1980. Human thyroid cancer: membrane thyrotropin binding and adenylate cyclase activity. J Clin Endocrinol Metab, 51:915–920.

29.

Balme

. 1954. Metastatic carcinoma of the thyroid successfully treated with thyroxine. Lancet, 266:812–813.

30.

Crile

Jr.

1966. Endocrine dependency of papillary carcinomas of the thyroid. JAMA, 195:721–724.

31.

Wang

, Wang

, Liu

, Chien

, Tung

, Lu

, Chen

, Lee

. 1999. Levothyroxine suppression of thyroglobulin in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab, 84:4549–4553.

32.

Sfakianakis

, Skillman

, George

. 1975. Thyroxine withdrawal in thyroid cancer. Ohio State Med J, 71:79–82.

33.

Goldberg

, Ditchek

. 1981. Thyroid carcinoma with spinal cord compression. JAMA, 245:953–954.

34.

Burmeister

, Goumaz

, Mariash

, Oppenheimer

. 1992. Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab, 75:344–350.

35.

Kamel

, Güllü

, Dağci Ilgin

, Corapçioğlu

, Tonyukuk Cesur

, Uysal

, Başkal

, Erdoğan

. 1999. Degree of thyrotropin suppression in differentiated thyroid cancer without recurrence or metastases. Thyroid, 9:1245–1248.

36.

Mazzaferri

, Massoll

. 2002. Management of papillary and follicular (differentiated) thyroid cancer: new paradigms using recombinant human thyrotropin. Endocr-Relat Cancer, 9:227–247.

37.

Hundahl

, Cady

, Cunningham

, Mazzaferri

, McKee

, Rosai

, Shah

, Fremgen

, Stewart

, Hölzer

. 2000. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer, 89:202–217.

38.

Biondi

, Cooper

. 2008. The clinical significance of subclinical thyroid disease. Endocr Rev, 29:76–131.

39.

Biondi

, Palmieri

, Klain

, Schlumberger

, Filetti

, Lombardi

. 2005. Subclinical hyperthyroidism: clinical features and treatment options. Eur J Endocrinol, 152:1–9.

40.

British Thyroid Association and Royal College of Physicians. 2007. Guidelines for management of thyroid cancer. www.btf-thyroid.org. 2007 December 1.

41.

American Association of Clinical

Endocrinologists

, American College of

Endocrinology

. 2001. Thyroid Carcinoma Taskforce AACE/AAES medical/surgical guidelines for clinical practice: management of thyroid carcinoma. Endocr Pract, 7:202–220.

42.

Kendall-Taylor

. Guidelines Working Group. 2003. Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf ), 58:400–402.

43.

Mazzaferri

, Jhiang

. 1994. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med, 97:418–428.

44.

Pujol

, Daures

, Nsakala

, Baldet

, Bringer

, Jaffiol

. 1996. Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab, 81:4318–4323.

45.

Cady

, Cohn

, Rossi

, Sedgwick

, Meissner

, Werber

, Gelman

. 1983. The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma. Surgery, 94:978–983.

46.

McGriff

, Csako

, Gourgiotis

, Lori

, Pucino

, Sarlis

. 2002. Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Ann Med, 34:554–564.

47.

Cooper

, Specker

, Ho

, Sperling

, Ladenson

, Ross

, Ain

, Bigos

, Brierly

, Haugen

, Klein

, Robbins

, Sherman

, Taylor

, Maxon

III . 1998. Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National Thyroid Cancer Treatment Cooperative Registry. Thyroid, 8:737–744.

48.

Jonklaas

, Sarlis

, Litofsky

, Ain

, Bigos

, Brierley

, Cooper

, Haugen

, Ladenson

, Magner

, Robbins

, Ross

, Skarulis

, Maxon

, Sherman

. 2006. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid, 16:1229–1242.

49.

Hovens

, Stokkel

, Kievit

, Corssmit

, Pereira

, Romijn

, Smit

. 2007. Associations of serum thyrotropin concentrations with recurrence and death in differentiated thyroid cancer. J Clin Endocrinol Metab, 92:2610–2615.

50.

Botella-Carretero

, Galan

, Caballero

, Sancho

, Escobar-Morreale

. 2003. Quality of life and psychometric functionality in patients with differentiated thyroid carcinoma. Endocr-Relat Cancer, 10:601–610.

51.

Biondi

, Fazio

, Carella

, Sabatini

, Amato

, Cittadini

, Bellastella

, Lombardi

, Saccà

. 1994. Control of adrenergic overactivity by β-blockade improves quality of life in patients receiving long term suppressive therapy with levothyroxine. J Clin Endocrinol Metab, 78:1028–1033.

52.

Biondi

, Fazio

, Cuocolo

, Sabatini

, Nicolai

, Lombardi

, Salvatore

, Saccà

. 1996. Impaired cardiac reserve and exercise capacity in patients receiving long-term thyrotropin suppressive therapy with levothyroxine. J Clin Endocrinol Metab, 81:4224–4228.

53.

Portella

, Silva

, Wagman

, Oliveira

, Buescu

, Vaisman

. 2006. Exercise performance in young and middle-aged female patients with subclinical hyperthyroidism. Thyroid, 16:731–735.

54.

Mercuro

, Panzuto

, Bina

, Leo

, Cabula

, Petrini

, Pigliaru

, Mariotti

. 2000. Cardiac function, physical exercise capacity, and quality of life during long-term thyrotropin-suppressive therapy with levothyroxine: effect of individual dose tailoring. J Clin Endocrinol Metab, 85:159–164.

55.

Hoftijzer

, Heemstra

, Corssmit

, van der Klaauw

, Romijn

, Smit

. 2008. Quality of life in cured patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab, 93:200–203.

56.

Tan

, Nan

, Thumboo

, Sundram

, Tan

. 2007. Health-related quality of life in thyroid cancer survivors. Laryngoscope, 11,7:507–510.

57.

Biondi

, Fazio

, Carella

, Amato

, Cittadini

, Lupoli

, Saccà

, Bellastella

, Lombardi

. 1993. Cardiac effects of long-term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab, 77:334–338.

58.

Shapiro

, Sievert

, Ong

, Ocampo

, Chance

, Lee

, Nanna

, Ferrick

, Surks

. 1997. Minimal cardiac effects in asymptomatic athyreotic patients chronically treated with thyrotropin-suppressive doses of L-thyroxine. J Clin Endocrinol Metab, 82:2592–2595.

59.

Ching

, Franklyn

, Stallard

, Daykin

, Sheppard MC Gammage

. 1996. Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis. Heart, 75:363–368.

60.

Botella-Carretero

, Gomez-Bueno

, Barrios

, Caballero

, García-Robles

, Sancho

, Escobar-Morreale

. 2004. Chronic thyrotropin-suppressive therapy with levothyroxine and short-term overt hypothyroidism after thyroxine withdrawal are associated with undesirable cardiovascular effects in patients with differentiated thyroid carcinoma. Endocr-Relat Cancer, 11:345–356.

61.

Gullu

, Altuntas

, Dincer

, Erol

, Kamel

. 2004. Effects of TSH-suppressive therapy on cardiac morphology and function: beneficial effects of the addition of beta-blockade on diastolic dysfunction. Eur J Endocrinol, 150:655–661.

62.

Smit

, Eustatia-Rutten

, Corssmit

, Pereira

, Frölich

, Bleeker

, Holman

, van der Wall

, Romijn

, Bax

. 2005. Reversible diastolic dysfunction after long-term exogenous subclinical hyperthyroidism: a randomized, placebo-controlled study. J Clin Endocrinol Metab, 90:6041–6047.

63.

Fazio

, Biondi

, Carella

, Sabatini

, Cittadini

, Panza

, Lombardi

, Saccà

. 1995. Diastolic dysfunction in patients on thyroid-stimulating-hormone suppressive therapy with levothyroxine: beneficial effect of ß blockade. J Clin Endocrinol Metab, 80:2222–2226.

64.

Shargorodsky

, Serov

, Gavish

, Leibovitz

, Harpaz

, Zimlichman

. 2006. Long-term thyrotropin-suppressive therapy with levothyroxine impairs small and large artery elasticity and increases left ventricular mass in patients with thyroid carcinoma. Thyroid, 16:381–386.

65.

Biondi

, Palmieri

, Lombardi

, Fazio

. 2002. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med, 137:904–914.

66.

Haider

, Larson

, Benjamin

, Levy

. 1998. Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death. J Am Coll Cardiol, 32:1454–1459.

67.

Levy

, Garrison

, Savage

, Kannel

, Castelli

. 1990. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl J Med, 322:1561–1566.

68.

Bonow

, Udelson

. 1992. Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management. Ann Intern Med, 117:502–510.

69.

Flynn

, Bonellie

, Jung

, Macdonald

, Morris

, Leese

. 2010. Serum thyroid-stimulating hormone concentration, morbidity from cardiovascular disease, fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab[Epub ahead of print]. (in press)

70.

Samuels

. 1998. Subclinical thyroid disease in the elderly. Thyroid, 8:803–813.

71.

Sawin

, Geller

, Wolf

, Belanger

, Baker

, Bacharach

, Wilson

, Benjamin

, D'Agostino

. 1994. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med, 331:1249–1252.

72.

Cappola

, Fried

, Arnold

, Danese

, Kuller

, Burke

, Tracy

, Ladenson

. 2006. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA, 295:1033–1041.

73.

Ladenson

. 1993. Thyrotoxicosis and the heart: something old and something new. J Clin Endocrinol Metab, 77:332–333.

74.

Stewart

, Hart

, Hole

, McMurray

. 2002. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med, 113:359–364.

75.

Staffurth

, Gibberd

, Fui

. 1977. Arterial embolism in thyrotoxicosis with atrial fibrillation. Br Med J, 10:688–690.

76.

Presti

, Hart

. 1989. Thyrotoxicosis, atrial fibrillation, and embolism, revisited. Am Heart J, 117:976–977.

77.

Benjamin

, Wolf

, D'Agostino

, Silbershatz

, Kannel

, Levy

. 1998. Impact of atrial fibrillation on the risk of death: the Framingham heart study. Circulation, 98:946–952.

78.

Stroke Risk in Atrial Fibrillation Working Group. 2007. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology, 69:546–554.

79.

Bauer

, Rodondi

, Stone

, Hillier

. 2007. Thyroid hormone use, hyperthyroidism and mortality in older women. Am J Med, 120:343–349.

80.

Haentjens

, Van Meerhaeghe

, Poppe

, Velkeniers

. 2008. Subclinical thyroid dysfunction and mortality: an estimate of relative and absolute excess all-cause mortality based on time-to-event data from cohort studies. Eur J Endocrinol, 159:329–341.

81.

Iervasi

, Molinaro

, Landi

, Taddei

, Galli

, Mariani

, L'Abbate

, Pingitore

. 2007. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med, 167:1526–1532.

82.

Radacsi

, Kovacs

, Bernard

, Feldkamp

, Horster

, Szabolcs

. 2003. Mortality rate of chronically ill geriatric patients with subnormal serum thyrotropin concentration: a 2-yr follow-up study. Endocrine, 21:133–136.

83.

Chubb

, Davis

. 2006. Subclinical hypothyroidism and mortality in women with type 2 diabetes. Clin Endocrinol, 64:476–477.

84.

Liewendahl

, Helenius

, Lamberg

, Mähönen

, Wägar

. 1987. Free thyroxine, free triiodothyronine, and thyrotropin concentrations in hypothyroid and thyroid carcinoma patients receiving thyroxine therapy. Acta Endocrinol (Copenh), 116:418–424.

85.

Jonklaas

, Davidson

, Bhagat

, Soldin

. 2008. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA, 299:769–777.

86.

Fish

, Schwartz

, Cavanaugh

, Steffes

, Bantle

, Oppenheimer

. 1987. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med, 316:764–770.

87.

Hughes

, Gallagher

, Olson

. 1989. Plasma free thyroxine concentrations in patients receiving levothyroxine for thyroid suppression. Surgery, 106:951–955.

88.

Taimela

, Koskinen

, Nuutila

, Nikkanen

, Saraste

, Taimela

, Irjala

. 1995. Free thyroid hormones and a third-generation TSH assay in the detection of hyperthyroidism during long-term thyroxine treatment in thyroid carcinoma patients. Scand J Clin Lab Invest, 55:181–186.

89.

Gammage

, Parle

, Holder

, Roberts

, Hobbs

, Wilson

, Sheppard

, Franklyn

. 2007. Association between serum free thyroxine concentration and atrial fibrillation. Arch Intern Med, 167:928–934.

90.

Gussekloo

, van Exel

, de Craen

, Meinders

, Frolich

, Westendorp

. 2004. Thyroid status, disability and cognitive function, and survival in old age. JAMA, 292:2591–2599.

91.

van den Beld

, Visser

, Feelders

, Grobbee

, Lamberts

. 2005. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab, 90:6403–6409.

92.

Vestergaard

, Rejnmark

, Weeke

, Mosekilde

. 2000. Fracture risk in patients treated for hyperthyroidism. Thyroid, 10:341–348.

93.

Franklyn

, Maisonneuve

, Sheppard

, Betteridge

, Boyle

. 1998. Mortality after the treatment of hyperthyroidism with radioactive iodine. N Engl J Med, 338:712–718.

94.

Ongphiphadhanakul

, Alex

, Braverman

, Baran

. 1992. Excessive L-thyroxine therapy decreases femoral bone mineral densities in the male rat: effect of hypogonadism and calcitonin. J Bone Miner Res, 7:1227–1231.

95.

Abe

, Marians

, Yu

, Wu

, Ando

, Li

, Iqbal

, Eldeiry

, Rajendren

, Blair

, Davies

, Zaidi

. 2003. TSH is a negative regulator of skeletal remodeling. Cell, 115:151–162.

96.

Bassett

, O'Shea

, Sriskantharajah

, Rabier

, Boyde

, Howell

, Weiss

, Roux

, Malaval

, Clement-Lacroix

, Samarut

, Chassande

, Williams

. 2007. Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism. Mol Endocrinol, 21:1095–1107.

97.

Quan

, Pasieka

, Rorstad

. 2002. Bone mineral density in well-differentiated thyroid cancer patients treated with suppressive thyroxine: a systematic overview of the literature. J Surg Oncol, 79:62–69.

98.

Heemstra

, Hamdy

, Romijn

, Smit

. 2006. The effects of thyrotropin-suppressive therapy on bone metabolism in patients with well-differentiated thyroid carcinoma. Thyroid, 16:583–591.

99.

Kung

, Yeung

. 1996. Prevention of bone loss induced by thyroxine suppressive therapy in postmenopausal women: the effect of calcium and calcitonin. J Clin Endocrinol Metab, 81:1232–1236.

100.

Müller

, Bayley

, Harrison

, Tsang

. 1995. Possible limited bone loss with suppressive thyroxine therapy is unlikely to have clinical relevance. Thyroid, 5:81–87.

101.

Guo

, Weetman

, Eastell

. 1997. Longitudinal changes of bone mineral density and bone turnover in postmenopausal women on thyroxine. Clin Endocrinol, 46:301–307.

102.

Fujiyama

, Kiriyama

, Ito

, Kimura

, Ashizawa

, Tsuruta

, Nagayama

, Villadolid

, Yokoyama

, Nagataki

. 1995. Suppressive doses of thyroxine do not accelerate age-related bone loss in late postmenopausal women. Thyroid, 5:13–17.

103.

Rachedi

, Rohmer

, Six

, Duquenne

, Wion Barbot

, Minebois

, Bigorgne

, Audran

. 1999. Prolonged suppressive L-thyroxine therapy. Longitudinal study of the effect of LT4 on bone mineral density and bone metabolism markers in 71 patients. Presse Med, 28:323–329.

104.

Jódar

, Begoña

López M

, García

, Rigopoulou

, Martínez

, Hawkins

. 1998. Bone changes in pre- and postmenopausal women with thyroid cancer on levothyroxine therapy: evolution of axial and appendicular bone mass. Osteoporos Int, 8:311–316.

105.

McDermott

, Perloff

, Kidd

. 1995. A longitudinal assessment of bone loss in women with levothyroxine-suppressed benign thyroid disease, thyroid cancer. Calcif Tissue Int, 56:521–525.

106.

Solomon

, Wartofsky

, Burman

. 1993. Prevalence of fractures in postmenopausal women with thyroid disease. Thyroid, 3:17–23.

107.

Bauer

, Ettinger

, Nevitt

, Stone

. 2001. Risk for the study of osteoporotic fractures. Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med, 134:561–568.

108.

Tamer

, Sargin

, Seker

, Babalik

, Tekce

, Yayla

. 2005. The evaluation of left ventricular hypertrophy in hypertensive patients with subclinical hyperthyroidism. Endocr J, 52:421–425.

109.

Dahl

, Danzi

, Klein

. 2008. Thyrotoxic cardiac disease. Curr Heart Fail Rep, 5:170–176.

110.

Estes

III , Halperin

, Calkins

, Ezekowitz

, Gitman

, Go

, McNamara

, Messer

, Ritchie

, Romeo

, Waldo

, Wyse

, Bonow

, DeLong

, Goff

Jr. , Grady

, Green

, Hiniker

, Linderbaum

, Masoudi

, Piña

, Pressler

, Radford

, Rumsfeld

. American College of Cardiology; American Heart Association Task Force on Performance Measures; Physician Consortium for Performance Improvement; ACC/AHA/Physician Consortium. 2008. Clinical performance measures for adults with non valvular atrial fibrillation or atrial flutter: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and the Physician Consortium for Performance Improvement developed in collaboration with the Heart Rhythm Society. J Am Coll Cardiol, 51:865–884.

111.

Belluzzi

, Sernesi

, Preti

, Salinaro

, Fonte

, Perlini

. 2009. Prevention of recurrent lone atrial fibrillation by the angiotensin-II converting enzyme inhibitor ramipril in normotensive patients. J Am Coll Cardiol, 53:24–29.

112.

Radford

, Arnold

, Bennett

, Cinquegrani

, Cleland

, Havranek

, Heidenreich

, Rutherford

, Spertus

, Stevenson

, Goff

, Grover

, Malenka

, Peterson

, Redberg

. American College of Cardiology; American Heart Association Task Force on Clinical Data Standards; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Failure Society of America. 2005. ACC/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with chronic heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards. Circulation, 112:1888–1916.

113.

Kung

, Yeung

. 1996. Prevention of bone loss induced by thyroxine suppressive therapy in postmenopausal women: the effect of calcium and calcitonin. J Clin Endocrinol Metab, 81:1232–1236.

114.

Schneider

, Barrett-Connor

, Morton

. 1994. Thyroid hormone use and bone mineral density in elderly women. Effects of estrogen. JAMA, 271:1245–1249.

115.

Rosen

, Moses

, Garber

, Ross

, Lee

, Ferguson

, Chen

, Lee

, Greenspan

. 1998. Randomized trial of pamidronate in patients with thyroid cancer: bone density is not reduced by suppressive doses of thyroxine, but is increased by cyclic intravenous pamidronate. J Clin Endocrinol Metab, 83:2324–2330.

116.

Panico

, Lupoli

, Fonderico

, Marciello

, Martinelli

, Assante

, Lupoli

. 2009. Osteoporosis and thyrotropin-suppressive therapy: reduced effectiveness of alendronate. Thyroid, 19:437–442.

117.

Lameloise

, Siegrist-Kaiser

, O'Connell

, Burger

. 2001. Differences between the effects of thyroxine and tetraiodothyroacetic acid on TSH suppression and cardiac hypertrophy. Eur J Endocrinol, 144:145–154.

118.

Sherman

, Gopal

, Haugen

, Chiu

, Whaley

, Nowlakha

, Duvic

. 1999. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med, 340:1075–1079.