In this study, we investigated the association between the severity of hypothyroidism and HRQL in newly diagnosed patients. A few previous studies found that ThyPRO scores correlate with the thyroid hormone levels, even within the normal range [9, 10], and with the level of thyroid autoantibodies [11]. Usually, graduation of the thyroid failure, for example into overt and subclinical hypothyroidism, is based on plasma levels of TSH and T4. To our knowledge, our study is the first to include the dynamics in plasma FT3I following LT4 treatment as a marker of perceived disease severity. In line with clinical observations, the dynamics in plasma FT3I reflected the extent of the thyroid failure. Thus, patients showing a decrease in FT3I following LT4 treatment (group A) had significantly higher FT4I at diagnosis compared with those showing an increase in plasma FT3I (group B). The difference between the two groups in the T3 dynamics is most likely due to adaptive differences in the DIO2 activity, as described above.

The main finding of our study is that patients with less pronounced hypothyroidism had significantly higher ThyPRO scores (i.e. worse HRQL) than those with biochemically more severe disease. Thus, FT4I at diagnosis correlated positively with ThyPRO scores in two scales. Depending on how patients were stratified according to disease severity, different items were affected, such as Hypothyroid Symptoms, Anxiety, Emotional Susceptibility, and Tiredness. Patients with subclinical hypothyroidism had a higher body weight than those with overt hypothyroidism, which potentially could have affected HRQL. However, this was not the case when patients where stratified based on the FT3I dynamics. Further, body weight was adjusted for in the regression analysis.

It is a paradox should patients with mild hypothyroidism have a worse HRQL than those with more severe disease. Therefore, we speculate that our finding may be due to selection bias, meaning that patients with a lower threshold for symptoms are being referred to a secondary center at an early stage of the disease. Most probably, such patients also have a gap in HRQL compared to the background population. A stratification of disease severity based on the FT3I dynamics showed more pronounced differences in HRQL than a conventional stratification into subclinical and overt hypothyroidism. This indicates that a stratification of hypothyroid patients by the former method may offer a more physiological approach, at least in the context of HRQL among newly diagnosed patients referred to an endocrine clinic. Potentially, the two ways of stratification may be complementary, as they seem to discriminate various items of ThyPRO-39 differently (Fig. 2).

Up to 80% of intracerebral T3 is derived from local conversion from T4 catalyzed by DIO2 [16, 29, 30], and it has been speculated that genetic variants of this enzyme are involved in the mental and cognitive symptoms characterizing some patients with AIT despite normal plasma TSH on LT4 substitution [16, 29, 30]. However, the majority of randomized placebo-controlled clinical trials comparing LT4 with LT4 + liothyronine (LT3) combination therapy failed to demonstrate any significant difference in HRQL between the two treatment regimens [7, 8, 29, 31]. Nevertheless, many patients treated for hypothyroidism have focus on T3 plasma levels, supported by ongoing media debates. Some patients may even have noticed that their plasma T3 level has declined after starting LT4 substitution therapy. In case of persistent fatigue or cognitive dysfunction, without any improvement by LT4 substitution, such patients may conclude that their symptoms are caused by the drop in plasma T3, thus requesting another treatment, e.g. LT4 + LT3 combination therapy. An important observation in our study—and of clinical relevance—is that patients with a decline in plasma T3 after LT4 treatment suffered from impaired HRQL. The difference in the dynamic in plasma T3 between group A and group B was most probably due to differences in the severity of hypothyroidism at diagnosis. If the two groups had been equally hypothyroid, the differences in HRQL and the plasma T3 dynamics might be more directly and causally related.

In contrast to most previous studies of patients with hypothyroidism, we used the extensively validated and disease specific ThyPRO-39 for measuring patient-reported outcomes [24]. In addition, the study was performed in a controlled clinical setting, including both men and women across a wide age range, and no other thyroid diseases than autoimmune thyroiditis were included. Limitations also exist. First, the study was not primarily designed to perform cross-sectional investigations of HRQL in relation to thyroid function tests. Thus, a sample size calculation was not performed specifically for the present study. However, we find that the risk of the study being statistically underpowered is low, as the patient subgroups differed significantly in several of the specified outcomes. Second, the patients had initiated LT4 treatment (within the last three months) before they filled-in the ThyPRO questionnaire. Eleven out of 67 patients had obtained biochemical euthyroidism when HRQL was assessed; however, excluding these individuals from the analysis did not significantly change the results (data not shown). Had the HRQL been assessed exactly at the time of diagnosis in all patients, the HRQL might have been more affected, potentially resulting in an even stronger correlation between HRQL and disease severity. Third, being enrolled in the CATALYST trial, half of the patients received 200 ug selenium per day, or placebo, respectively, in addition to the LT4 substitution. It can be argued that selenium could have influenced the T4 to T3 conversion and thus the plasma T3 level. However, we previously showed, in a large, randomized placebo-controlled trial, that selenium supplementation had no effect on either plasma FT3 level or the plasma FT3/FT4 ratio [32]. Fourth, although the coefficient of variation of measurement of T3 was at the same level as that of T4, T3 is more prone to fluctuations than T4 due to the influence of non-thyroidal illness [33, 34]. However, we consider these factors to be of minor relevance as individuals with major comorbidities and those receiving drugs with impact on the thyroid were excluded from the study. Further, excluding the six patients on estrogen containing drugs did not change our results. Finally, HRQL was assessed only initially and not after stable euthyroidism was achieved. Thus, it is unknown whether the two groups of patients, independent of the method used for stratification, achieved a similar HRQL after being euthyroid for a longer period.

In conclusion, in this study population, patients with more severe hypothyroidism at diagnosis had better HRQL compared to patients with milder hypothyroidism. The difference in HRQL was more pronounced if patients were stratified based on the FT3 dynamics following LT4 therapy as compared to the conventional approach, i.e. subclinical or overt hypothyroidism based on thyroid function tests at diagnosis. Our findings may reflect selection bias with an early referral of vulnerable patients to a secondary care center, where an initial decrease in plasma T3 is a common biochemical response to LT4 treatment.