Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects

Abstract

Background: There has been recent debate within the thyroid field regarding whether current upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. One important target organ for thyroid hormone is the brain, but little is known about variations in neurocognitive measures within the reference range for thyroid function.Methods: This was a cross-sectional study of 132 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (LT4) who had TSH levels across the full span of the laboratory reference range (0.34-5.6 mU/L). Subjects underwent detailed tests of health status, mood, and cognitive function, with an emphasis on memory and executive functions. Results: Subjects with low-normal (£2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ on most tests of health status, mood, or cognitive function, and there were no correlations between TSH, free T4, or free T3 levels and most outcomes. There was, however, a suggestion that thyroid function affected performance on the Iowa Gambling Task, which mimics real life decision-making. Subjects with low-normal TSH levels made more advantageous decisions than those with high-normal TSH levels. Conclusions: Variations in thyroid function within the laboratory reference range do not appear to have clinically relevant effects on health status, mood, or memory in LT4 treated subjects. However, decision making, which encompasses many executive functions, may be affected. Unless further studies strengthen this finding, these data do not support narrowing the TSH reference range.

A post-publication analysis of the idealized upper reference value of 2.5 mIU/L for TSH: Time to support the thyroid axis with magnesium and iron especially in the setting of reproduction medicine

“…In relation to coronary heart disease Åsvold et al [16] (n = 55,412) have observed that lowering the upper TSH reference value did not show any association with events of coronary heart disease. A similar observation has been made by Samuels et al [17] (n = 132) in relation to health status, cognition and mood. Walsh et al [18] evaluated whether changing the dose of thyroxine treatment can have an effect on well-being.…”

Reference range: Which statistical intervals to use?

“…where the random variables Z and v 2 in equation (5) are the same as those in equation (4). The R package tolerance 24,25 can be used to compute c 5 .…”

“…For example, underestimating the upper limit of a reference range would mean classifying a large number of people as diseased, thus affecting the doses of medication prescribed. 4 Construction of appropriate reference ranges is therefore crucial in laboratory medicine practice. Well-known general references 3 , 5 – 9 and a case for teaching tolerance intervals in introductory statistics courses 10 are available.…”

Applying a systems approach to thyroid physiology: Looking at the whole with a mitochondrial perspective instead of judging single TSH values or why we should know more about mitochondria to understand metabolism

“…patients remain symptomatic despite having normal thyroid hormone levels. Similar to the opinion of Kopp, Mary H. Samuels recently stated the following: “It is a common clinical observation that some otherwise healthy patients with hypothyroidism continue to complain of fatigue, poor mood, inability to concentrate, and vague cognitive difficulties (often described as “brain fog”) despite normal TSH levels” [67] . Similar comments have been made by other authors in the past [68] , [69] .…”