By: Dr. Geoffrey Modest
The US Preventive Services Taskforce (USPSTF) just published an update of their recommendations for TSH screening of nonpregnant, asymptomatic adults (see doi:10.7326/M15-0483). For formal USPSTF recommendation, see here.
–hypothyroidism: subclinical = asymptomatic, serum TSH between 4.5-10 (varies a bit by lab), and normal T3 and T4; overt = can be asymptomatic, but high TSH and low T4 levels
–hyperthyroidism: subclinical = asymptomatic, TSH < 0.4 and normal T3 and T4. subdivided into “low but detectable”, with TSH 0.1-0.4, and “undetectable” with TSH <0.1. overt= can be asymptomatic, but has elevated T3 or T4
–Detection: TSH is good for detection of thyroid abnormalities in the general population, but there is measurement variability with TSH (eg, one study did find that TSH levels can vary by as much as 50% on a day-to-day basis. Also, TSH is sensitive to non-thyroidal factors such as being suppressed by acute illness or meds ). Best to confirm asymptomatic abnormalities with repeat confirmatory tests in 3-6 months (except if TSH>10 or <0.01 per other recommendations, though I do tend to repeat prior to further workup or therapy, just to make sure…)
–Benefits of early detection: inadequate evidence that there is clinical benefit in nonpregnant, asymptomatic adult. ie, no clear RCT evidence that detecting abnormalities/doing something improves quality of life, or improves blood pressure, BMI, cognition, bone mineral density or lipid levels (more later)
–Adverse effects of screening include labeling, false-positive results, and overdiagnosis and overtreatment
–Overall assessment: not enough information to recommend screening
— They also note:
–subclinical hypothyroidism is common: 5% of women and 3% of men in US, increasing incidence with aging
–37% of people with subclinical hypothyroidism spontaneously revert without intervention after several years; 2-5% go on to develop overt hypothyroidism
–subclinical hyperthyroidism in about 0.7% of the US population, more in women than men (again, increases with aging)
–1/3 of those with subclinical hyperthyroidism revert to normal over time. 1-2% with TSH<0.1 go on to overt hyperthyroidism. less likely if TSH 0.1-0.45
–39% of people with TSH of 5.1-10 in a 1996 study received treatment, other data shows increasing % on meds as they age. (This is despite recommendations to the contrary – ie, from their perspective, many people are being treated without clear data)
–risk factors for hypothyroidism in the US (most are from Hashimoto’s thyroiditis) are age, female sex, white race, type 1 diabetes, Down syndrome, family history, goiter, neck irradiation
–risk factors for hyperthyroidism include age, female sex, black race, low iodine intake, ingestion of iodine-containing drugs (eg amiodarone)
This brings up a few issues:
–The USPSTF is pretty stringent in making recommendations, in general requiring high quality positive RCTs to make a strong recommendation. The plus here is that the recommendation is more evidence-based. The minus is that there are lots of things we do (or should do) which just have not had the studies done to back them up. So, the fact that they find insufficient evidence in the case of thyroid screening does not necessarily mean that it should not be done. For TSH screening, I basically agree — there really is not enough evidence and studies should be done, especially given how common the issue is.
–One big issue is what is the normal TSH???. A large observational study based on the Natl Health and Nutrition Exam Survey III (see J Clin Endocrinol Metab 92: 4575, 2007) looked specifically at people of different ages who were “disease-free” (no report of thyroid disease, goiter, or taking thyroid meds) and negative antibodies (no thyroid peroxidase or thyroglobulin antibodies, which are typically present with Hashimoto’s thyroiditis), and were not overtly hyper- or hypothyroid (ie, TSH not >10 or <.01). They looked at the distribution of TSH values per different age groups. It turns out that the plot by age shows a shift in the median and 97.5th percentile noted with aging (a shift to a higher TSH), which suggests that TSH does normally increase with age, and in a step-wise manner by age group. The issue here is that there is more actual thyroid disease with aging, but that if it were just a larger number of people with high TSH, the median should still be in the “normal” place but with a longer tail for the increased incidence of actual thyroid disease. By their analysis if one uses a TSH >4.5 mIU/L as the cutpoint, “70% of the raised values for the 80-yr and older group fall within the 97.5 centile of their age-specific range” (by the way, some smaller studies do not find this. One confounding issue is that the elderly also can have more subclinical hyperthyroidism, which would also affect the median TSH). Other issues which suggest this increasing “normal” TSH is that only a small percentage (about 2.5%/year) actually do develop overt hypothyroidism (TSH>10), even over a 20-year study. The reason for increasing TSH with aging???? could be medical issues or meds which interfere with the efficiency/sensitivity of the hypothalamic-pituitary feedback system. Or may be a part of healthy aging (slowing down the metabolism to preserve bodily function — though hard to make a strong evolutionary argument here, since not many 70-year olds are strong participants in furthering the species, and the % of the population with TSH>4.5 really begins to climb at age 70).
–Subclinical hypothyroidism: the potential for detection and treatment is more theoretical, since there are no significant longterm studies with many of the important clinical endpoints to inform practice. There have been a couple of short-term studies on treating subclinical hypothyroidism, showing no effect on blood pressure. Studies on lipids are mixed, but show small effect if any (hypothyroidism is assoc with high LDL). in terms of cardiac effects, one large UK observational study (Arch Intern Med 2012; 172:811) looked at 4735 people with subclinical hypothyroidism (based on a single TSH value of 5-10), followed for 7.6 years, 1/2 on thyroid meds, and found that in those 40-70 yo, 4.2% of those on thyroid meds had ischemic heart disease events vs 6.6% not on meds (a significant HR=0.61). No significant difference in those >70yo. But they did not account for other meds (statins, aspirin…) which are likely to be different in the >70yo crowd, and this was not an RCT. Of interest, they also found less cancer deaths with thyroxine therapy in the younger group (??suggesting confounding in the study). Some, but not all studies have also found some benefit in the surrogate markers of endothelial function, LV diastolic function. There are also a few studies finding increased heart failure, with a trend in those in the TSH 7-10 range but significant in those in the 10-20 range. But again there are no intervention studies showing benefit to treatment.
–Subclinical hyperthyroidism: autonomous adenomas and multinodular goiters (MNG) are more common causes (one study had 57% of patients with MNG), though overtreatment of hypothyroidism is still a very common cause. 40-60% spontaneously revert over weeks to years (?if they had thyroiditis). In terms of risk for fractures, the effect of T4 is predominantly in cortical bone (eg wrist), least in trabecular (spine) and in-between in mixed (hip). The observational data in a recent study on hip or nonspine fracture was not significantly elevated with subclinical hyperthyroidism (see Ann Intern Med 2014; 161: 189). Other studies have shown bone effect of hyperthyroidism, which tracks with degree of TSH suppression. Atrial fibrillation is a major concern, with increased risk of about 70%, also tracking with the degree of TSH suppression, but clearly present with subclinical hyperthyroidism. Also, heart failure is associated with subclinical hyperthyroidism. Observational data are mixed for mortality, dementia, quality of life. So, clearest concern is from afib, though we still do not have adequate data on preemptive treatment leading to benefit.
–In terms of adverse effects of labeling/treating: one study found that of 34K women with known hypothyroidism were less likely to report good self-rated health (not clear that this would apply to subclinical patients, but probably…). Also, a study from 2004 found that 1/4 of patients on levothyroxine were inadvertently on too high a dose (TSH undetectable). Raises unproven potential for fractures or afib.
–One concern I have about asymptomatic vs symptomatic is that it is often hard to tell the difference. Most of the symptoms of both hypo and hyperthyroidism, esp in milder cases, are very nonspecific. And the patient may not even see these as symptoms, since they come on very gradually and the patient may just adapt to them.
–So, how does one piece this all together?? It is clear that we really need long-term RCTs to figure this out. Observational trials can be misleading. And subclinical thyroid dysfunction is such a common condition with such potentially bad outcomes that it is pretty striking it has not been studied (though I suppose that there’s not much $$ for drug companies in it, given generic availability….). The big issue for me is the very real question of what a normal TSH is. One could argue that it might be reasonable to check TSH some time after a patient reaches the ripe old age of 50 just to make sure they don’t have overt thyroid disease and treat that. But if the TSH is in the subclinical region, repeat it in a year. And if okay, maybe repeat in 5 years. This approach acknowledges that even overt thyroid disease, which most believe should be treated, is pretty common and often will not be detected without looking for it. Above and beyond this population approach, it is certainly reasonable based on the above to use targeted testing — eg, if patient has some potentially associated finding (hyponatremia, increased CK, macrocytic anemia, autoimmune disorder, pericardial/pleural effusion, etc, and perhaps even high LDL)