[R] How should SH be managed?

[R] How should SH be managed?

[R1] Frequency and causes of SH

SH has a prevalence of about 1% in the general population (245). In older persons, TMNG is probably the most common cause of SH, with other etiologies of endogenous SH, including GD, solitary autonomously functioning nodules, and various forms of thyroiditis (246,247), the latter of which would be more strictly termed ''subclinical thyrotoxicosis.'' Some otherwise healthy older persons may have low serum TSH levels, low normal serum levels of free T4 estimates and T3, and no evidence of thyroid or pituitary disease, suggesting an altered set point of the pituitary-thyroid axis (248,249). This situation can mimic SH biochemically, and it may be difficult to rule out clinically, although scintigraphic studies suggesting autonomous thyroid function would favor SH. Other causes of a suppressed TSH but normal estimated free T4 and T3 include corticosteroid therapy, central hypothyroidism, and nonthyroidal illness.

Once SH has been detected, it is important to document that it is a persistent problem by repeating the serum TSH at 3 or 6 months. Some reports suggest that a subnormal serum TSH may spontaneously resolve, especially if the levels are >0.05mU/L (250–252). Patients with GD rather than a TMNG as the cause of SH may be more likely to spontaneously remit (253).

[R2] Clinical significance of SH

Since SH is a mild form of hyperthyroidism, deleterious effects on the cardiovascular system and the skeleton might be expected in some patients, and subtle symptoms of thyrotoxicosis or altered cognition might also be potential problems. Regarding cardiac complications, one study found a 2.8-fold risk of atrial fibrillation in persons over age 60 years with SH (254), which has been confirmed in another population over age 65 years (255). Small uncontrolled studies have shown improvement in cardiac parameters,with restoration of a euthyroid state (256,257) or the use of beta adrenergic blocking drugs (258).

Postmenopausal women with SH may have increased fracture rates even with only mildly suppressed serum TSH levels (259), as well as improvement in bone mineral density with therapy of SH with antithyroid drugs or radioactive iodine in controlled but nonrandomized intervention studies (260,261). There are also preliminary data suggesting an increase in bone turnover (262) and lower bone density in premenopausal women with SH (263). Another uncontrolled study has shown an increase in muscle mass and muscle strength in middle-aged women with SH after treatment with radioactive iodine or thyroidectomy (264). For patients receiving levothyroxine replacement therapy, only those with a suppressed TSH had an increased risk of cardiac or bone disease, whereas those with a low, but unsuppressed level did not (265).

One cross-sectional (266) and one longitudinal (267) study of older individuals showed no changes in cognitive function, whereas two others suggested an association between SH and dementia in older persons (268,269). Finally, there is the potential risk of progression to overt hyperthyroidism if SH is left untreated. This risk is probably somewhere between 0.5% and 1% per year (270,271).

Data on the effects of SH on mortality are conflicting. In one study, all-cause and cardiovascular mortality were higher in a group of individuals with SH(serum TSH<0.5mU/L) aged 60 years and older at 1, 2, and 5 years of follow-up, but not after 10 years of follow-up (271). Another study also found an increase in mortality over 4 years of follow-up among persons aged 85 years and above (267), in a third study, individuals with SH and concomitant heart disease had an increase in cardiovascular and all-cause mortality (272). In contrast, two other longitudinal population-based studies reported no increase in overall mortality in persons with SH (255,273). A recent meta-analysis suggested that all-cause mortality risk in SH progressively increases with age (274), which might explain the conflicting reports. Another meta-analysis, however, did not find a statistically significant increase in mortality in SH (275).

[R3] When to treat SH

  • RECOMMENDATION 65
    When TSH is persistently <0.1 mU/L, treatment of SH should be strongly considered in all individuals 65 years of age, and in postmenopausal women who are not on estrogens or bisphosphonates; patients with cardiac risk factors, heart disease or osteoporosis; and individuals with hyperthyroid symptoms. 2/++0

Treatment of SH is controversial, since no controlled intervention studies to show benefit have been performed. However, a panel of experts determined that the evidence for benefit was sufficient to warrant therapy of SH in older individuals whose serum TSH level was <0.1mU/L (276). This was based primarily on the studies showing an increased rate of atrial fibrillation and altered skeletal health with a suppressed level of TSH described above.

There are insufficient data for or against treatment of SH in younger persons or premenopausal women with SH and serum TSH <0.1mU/L. One uncontrolled study of middle-aged patients showed an improvement in hyperthyroid symptoms with therapy (256). Although this study did not include younger individuals, the task force elected to recommend treatment of all SH patients younger than 65 years of age with persistent TSH <0.1mU/L and hyperthyroid symptoms.

Technical remarks: A TSH level of <0.1mU/L on repeated measurement over a 3–6-month period is considered to be persistent, effectively ruling out transient thyroiditis as a cause. The thyroid disorder underlying SH should be diagnosed, and is most commonly TMNG, GD, or TA.

  • RECOMMENDATION 66
    When TSH is persistently below the lower limit of normal but 0.1 mU/L, treatment of SH should be considered in individuals 65 years of age and in patients with cardiac disease or symptoms of hyperthyroidism. 2/+00

Since the publication of the expert panel report discussed above, a subsequent study showed that a higher risk of atrial fibrillation may extend to persons over age 65 years who have serum TSH levels between 0.1 and 0.5mU/L (where 0.5mU/ L is the lower limit of the normal range for the assay) (255). Therefore, justification for therapy in patients with this higher TSH threshold level rests with those data, as well as a meta-analysis showing a progressive increase in mortality in individuals older than 60 years of age (274). In contrast, an observational cohort study of T4-treated patients could find no such relationship with TSH levels between 0.04 and 0.4mU/L. There are no data for or against treatment of individuals younger than middle-aged with serum TSH levels between 0.1 and 0.5mU/L. In patients with symptoms of hyperthyroidism, a trial of beta-adrenergic blockers may be useful to determine whether symptomatic therapy might suffice.

Technical remarks: A TSH level between 0.1 and 0.5mU/L on repeated measurement over a 3–6-month period is considered persistent, effectively ruling out transient thyroiditis as a cause. The thyroid disorder underlying SH with TSH persistently within this range should be diagnosed to avoid treating patients with transient, functional disorders related to acute illness, drugs, and other causes of low TSH. A summary of factors to consider when deciding whether or not to treat a patient with SH is provided (Table 8).

[R4] How to treat SH

  • RECOMMENDATION 67
    If SH is to be treated, the treatment should be based on the etiology of the thyroid dysfunction and follow the same principles as outlined for the treatment of overt hyperthyroidism. 1/+00

The treatment of SH is similar to the treatment of overt hyperthyroidism. Radioactive iodine is appropriate for most patients, especially in older patients when TMNG is a frequent cause of SH. There are no data to inform whether elderly patients with SH would benefit from pretreatment with ATDs to normalize thyroid function before radioactive iodine therapy. Given the low risk of exacerbation (51), the risks of ATD therapy may outweigh any potential small benefit. Long-term ATD therapy is a reasonable alternative to radioactive iodine in patients with GD and SH, especially in younger patients, since remission rates are highest in persons with mild disease (81). Some patients with SH due to GD may remit spontaneously without therapy, so that continued observation without therapy is reasonable for younger patients with SH due to GD. A small subset of elderly patients with persistently low TSH and no evidence of true thyroid dysfunction can be followed without intervention, especially when the serum FT4 estimate and T3 levels are in the lower half of the normal range. Treatment with beta-adrenergic blockade may be sufficient to control the cardiovascular-related morbidity from SH, especially that of atrial fibrillation (258).

Technical remarks: Some patients with SH due to mild GD may remit spontaneously and may be followed without therapy with frequent (every 3 months) monitoring of thyroid function. In select patients with SH due to TMNG who have compressive symptoms, or in whom there is concern for malignancy, surgery is also an option.

[R5] End points to be assessed to determine effective therapy of SH

The goal of therapy for SH is to render the patient euthyroid with a normal TSH. Since the rationale for therapy of SH is to a large degree preventive, there are few end points that can be used to document that therapy has been successful. There are no studies to show that therapy prevents the onset of atrial fibrillation or decreases mortality. Several studies have shown stabilization or improvement in bone mineral density with therapy of SH in postmenopausal women (260,261,277). One uncontrolled study reported an improvement in hyperthyroid symptoms with antithyroid drug therapy of SH (256) and a second report showed improvement in the hyperthyroid symptoms of SH after treatment with beta-adrenergic blockade (258).

TABLE 8. SUBCLINICAL HYPERTHYROIDISM: WHEN TO TREAT

Factor

TSH (<0.1 mU/L)

TSH (0.1–0.5 mU/L)a

Age > 65

Yes

Consider treating

Age < 65 with comorbidities

 

 

  Heart disease

Yes

Consider treating

  Osteoporosis

Yes

No

  Menopausal

Consider treating

Consider treating

  Hyperthyroid symptoms

Yes

Consider treating

Age < 65, asymptomatic

Consider treating

No

aWhere 0.5mU/L is the lower limit of the normal range.