Abstract
Purpose: Low T3 syndrome is defined by a fall in free triiodothyronine (FT3) in spite of normal serum thyroid-stimulating hormone (TSH) and often normal free thyroxin (FT4). A low FT3/FT4 ratio, a relevant marker for low T3 syndrome, is known as a risk of mortality in hemodialysis (HD) patients, as well as low muscle mass in the general population. Because of the local activation of T4 to FT3 in muscle tissue, we examined the association of FT3/FT4 ratio with serum creatinine, a marker of muscle mass and strength in HD patients to investigate the significance of muscle tissue in the development of low T3 syndrome in HD patients. Methods: This was a cross-sectional study derived from our prospective cohort study, named DREAM, of Japanese HD patients. After the exclusion of patients with treated and untreated thyroid dysfunction, 332 patients were analyzed in the study. Results: The serum FT4 and TSH of HD patients (n = 332) were 0.9 ± 0.1 ng/dL. and 2.0 ± 0.9 μIU/mL, which were within the respective normal range, while serum FT3 was 2.2 ± 0.3 pg/mL. As many as 101 out of 332 (30.4%) HD patients exhibited a serum FT3 less than the normal lower limit of 2.2 pg/mL. The serum FT3/FT4 ratio correlated significantly positively with serum creatinine, and inversely with serum log CRP and total cholesterol, while it exhibited a tendency towards positive correlation with serum albumin. Multiple regression analysis, which included serum creatinine, albumin, and log CRP, simultaneously, in addition to sex, age, diabetic kidney disease or not, log HD duration, body mass index, systolic blood pressure, and Kt/V, as independent variables, revealed an independent and significant positive association of serum creatinine, but not serum albumin or CRP, with the serum FT3/FT4 ratio. Conclusions: The present study demonstrated an independent and positive correlation of serum creatinine with the serum FT3/FT4 ratio in HD patients. The lack of association of the serum FT3/FT4 ratio with serum albumin and CRP suggested the presence of a creatinine-specific mechanism to associate with serum FT3/FT4 ratio. Because of the local activation of T4 to T3 at muscle tissue, a lower muscle mass may be causatively associated with low T3 syndrome.
Highlights
Chronic kidney disease (CKD) is often associated with an alteration in thyroid hormone status, leading to the development of euthyroid sick syndrome or low triiodothyronine (T3) syndrome [1,2], the latter of which is characterized by a fall in free T3 (FT3) in spite of serum levels of thyroid-stimulating hormone (TSH) and free thyroxin (FT4) maintained within normal ranges [3]
The present study demonstrated an independent association of lower serum creatinine, but not of albumin or log CRP, with a lower serum FT3/FT4 ratio in Japanese HD
The HD patients enrolled in the present study were restricted to those with normal TSH, though it is becoming increasingly recognized that serum FT3 is more important than serum TSH for evaluating thyroid gland function because of its direct action in the target tissue [22]
Summary
Chronic kidney disease (CKD) is often associated with an alteration in thyroid hormone status, leading to the development of euthyroid sick syndrome or low triiodothyronine (T3) syndrome [1,2], the latter of which is characterized by a fall in free T3 (FT3) in spite of serum levels of thyroid-stimulating hormone (TSH) and free thyroxin (FT4) maintained within normal ranges [3]. The mechanism by which serum FT3 decreases relative to serum FT4 in spite of normal TSH is mainly explained by a decreased T4 to T3 deiodination process caused by various factors, such as inflammation and malnutrition [12], mainly in skeletal muscle [13]. It was recently shown in an aged population that sarcopenia might be associated with reduced T4 to T3 deiodination due possibly to smaller site of deiodination [14]. The rate of the process of T4 to T3 deiodination in low T3 syndrome cases is known to be represented by the serum FT3/FT4 ratio [14,15], The present cross-sectional study examined (i) the prevalence of low T3 syndrome in Japanese hemodialysis patients, and (ii) the identification of the most important factor among sarcopenia, malnutrition, or inflammation to associate with a reduced serum
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