Low free thyroxine concentratios and deficient nocturnal surge of thyroid-stimulating hormone in haemodialysed patients compared with undialysed patients
Katsuhiko Yonemura,
Toshiaki Nakajima1,
Takayuki Suzuki1,
Shinichiro Ando2,
Rieko Genma2,
Hirotoshi Nakamura2 and
Akira Hishida1
Hemodialysis Unit,
1 First Department of Medicine and
2 Second Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Abstract
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Background. There is little information on the differences in pituitarythyroid function between undialysed and haemodialysed patients.
Methods. Serum concentrations of free thyroxine (T4) and free triiodothyronine (T3), measured by enhanced chemiluminescence immunoassay, and thyroid-stimulating hormone (TSH) were compared in undialysed (n=22) and haemodialysed patients (n=85). The response of the serum TSH concentration to exogenously administered thyrotropin-releasing hormone (TRH) and circadian variation in serum TSH were also studied in the two groups.
Results. Serum free T4 concentration was significantly lower in haemodialysed than in undialysed patients (1.02±0.02 vs 1.33±0.06 ng/dl, P<0.0001). Serum concentrations of free T3 and TSH were essentially the same for the two groups. The response of serum TSH concentration to TRH was basically the same. Serum TSH concentration in undialysed patients during the night and in the morning were 142.4±15.4% and 121.7±4.1% of that during the day, the differences being significantly different. A nocturnal surge of TSH was not observed in haemodialysed patients.
Conclusions. Low serum free T4 concentration and a deficient nocturnal surge of TSH were found in haemodialysed patients compared with undialysed patients. The deficient nocturnal surge of TSH may contribute to the lower serum free T4 concentration in haemodialysed patients.
Keywords: chronic renal failure; haemodialysis; thyroid hormone; thyroid-stimulating hormone
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Introduction
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Previous studies on thyroid function tests indicate lower thyroid hormone concentrations with normal thyroid-stimulating hormone (TSH) in haemodialysed patients compared with normal subjects [16]. Analogue radioimmunoassay for measurement of thyroid hormone in such studies was affected by the serum albumin concentration [79] and resulted in spuriously low serum concentrations of free thyroxine (T4) and free triiodothyronine (T3) in patients with various non-thyroidal illness such as malignant diseases, heart failure, renal failure and bacterial infection [10]. Low serum albumin concentration is often found in patients with end-stage renal disease (ESRD). Data for thyroid hormone obtained in patients with ESRD may thus not reflect thyroid function accurately [1113]. The results of a recently developed enhanced chemiluminescence immunoassay for measurement of free thyroid hormone are not significantly altered by serum albumin concentration [12]. There is little information about thyroid function tests determined by this assay in patients with ESRD [14].
Low thyroid hormone with normal serum concentration of TSH possibly may be due to impaired TSH secretion. In fact, a blunted response of serum TSH concentration to thyrotropin-releasing hormone (TRH) injection [11,1518] and a deficient nocturnal surge of TSH [5,19] have been observed in haemodialysed patients. Whether these abnormalities in pituitarythyroid function occur in undialysed patients remains unclear. Furthermore, there have not been any studies in which pituitarythyroid function has been compared between undialysed and haemodialysed patients.
Thus, in the present study, pituitarythyroid function measured by enhanced chemiluminescence immunoassay, TSH secretion estimated by response to TRH injection, and circadian variation were evaluated in undialysed and haemodialysed patients.
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Patients and methods
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Twenty-two undialysed patients (mean creatinine clearance: 21.2±2.3 l/day, range 7.547.6 l/day) and 85 haemodialysed patients (mean duration of dialysis: 12.3±0.7 months, range 123 months) participated in the present study with informed consent. Patients with known thyroid diseases or severe illnesses were excluded. All patients were clinically euthyroid and well nourished. Clinical and laboratory features of the patients in the two groups are presented in Table 1
. All haemodialysed patients were on thrice-weekly 4 h dialysis. Unfractionated heparin was used as an anticoagulant. Bicarbonate dialysate was used, and dialysis water was prepared by reverse osmosis. Results of the thyroid function tests including serum concentrations of free T3, free T4 and TSH were compared for the two groups.
All blood samples were obtained in the morning before breakfast and before haemodialysis (HD) therapy. Serum was stored at -20°C until assay. Serum free T3 concentration (reference range: 2.404.00 pg/ml) and free T4 concentration (reference range: 0.851.72 ng/dl) were measured using the Amerlite-MAB Free T3 and Amerlite-MAB Free T4 kits (Ortho-Clinical Diagnostics Ltd, Amersham, UK), respectively. Serum TSH concentration (reference range: 0.44.7 mU/l) was measured by the TSH 60 kit (Ortho-Clinical Diagnostics Ltd, Amersham, UK).
The response of serum TSH concentration to TRH was studied in 10 undialysed patients and 25 haemodialysed patients. Serum TSH concentration was determined before and 15, 30, 60 and 120 min after injection of 0.5 mg of synthetic TRH. For evaluation of circadian variation in serum TSH concentration, blood samples were obtained in the morning (0800 and 0900 h), during the day (1400 and 1500 h) and during the night (0200 and 0300 h) for 12 undialysed and eight haemodialysed patients. All determinations were made on days when HD therapy was not conducted.
All data were expressed as the mean±SE. Mean values of the thyroid function test and circadian variation in serum TSH were analysed by unpaired Student's t-test and paired Student's t-test, respectively. Statistical comparison of the response of TSH to TRH was made using analysis of variance (ANOVA). Statistical comparison of ratios was carried out by the
2 test. P<0.05 was considered significant.
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Results
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The results of the thyroid function tests are shown in Table 2
. Free T4 concentration was significantly lower in haemodialysed patients than in undialysed patients (1.02±0.02 vs 1.33±0.06 ng/dl, respectively, P<0.0001). Although the serum TSH concentration was usually less in haemodialysed patients than in undialysed patients, the serum concentrations of free T3 and TSH were essentially the same for both sets of patients. The free T4 concentration was not below the reference range in any of the 22 undialysed patients but was below this range in 13 (15%) of the 85 haemodialysed patients (P=0.05). The prevalence of the serum free T3 concentration below the reference range was the same for the two groups (13.6% in undialysed patients and 11.8% in haemodialysed patients, P=0.81). No significant correlation could be detected between serum free T4 concentration and creatinine clearance in undialysed patients, as shown in Figure 1
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Fig. 1. Relationship between free T4 and creatinine clearance (Ccr) in Group 1. No significant relationship could be found between these parameters (r=0.174, P=0.44).
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The results of response of serum TSH to TRH injection are shown in Figure 2
. Baseline and peak values of serum TSH concentration at 60 min after injection of 0.5 mg of TRH showed no significant difference for the two groups (1.73±0.32 and 8.13±1.76 mU/l in undialysed, and 1.83±0.19 and 7.44±0.66 mU/l in haemodialysed patients, respectively).

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Fig. 2. Response of serum TSH to injection of 0.5 mg of TRH in haemodialysed and undialysed patients. The response in undialysed (solid line) and haemodialysed patients (dotted line) was essentially the same.
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Circadian variation in serum TSH concentration is shown in Figure 3
. Although the serum concentrations of free T3 and TSH were the same for the two groups (2.59±0.13 vs 2.84±0.11 pg/ml in undialysed, and 2.24±0.56 vs 1.90±0.27 mU/l in haemodialysed patients), serum free T4 concentration was significantly lower in haemodialysed than in undialysed patients (1.01±0.04 vs 1.29±0.13 ng/dl, P=0.0076). Serum TSH concentration in undialysed patients during the night and in the morning were 142.4±15.4% and 121.7±4.1% of that during the day, significantly exceeding day time values (P=0.0186 and P=0.0002, respectively). Values during the night, in the morning and during the day in haemodialysed patients were essentially the same.

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Fig. 3. Circadian variation in serum TSH in undialysed patients (n=8) (closed columns) and haemodialysed patients (n=12) (open columns). Serum TSH during the night and in the morning was expressed as a percentage of daytime values. Serum TSH in the morning was 2.08±0.48 mU/ml in undialysed patients and 1.27±0.22 mU/ml in haemodialysed patients (P=0.202). Circadian variation in serum TSH was observed in undialysed patients, but not in haemodialysed patients.
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Discussion
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Free thyroid hormone in serum is regarded as an important determination of the thyroid status. Inconsistent data for thyroid function tests in patients with ESRD may be accounted for by how they were assayed. Since serum free concentrations of T3 and T4 with analogue radioimmunoassay are affected by serum albumin concentration [779] and use of heparin [4,20], this assay resulted in spuriously low free thyroid hormone in patients with ESRD [1013], in whom low serum albumin concentration is often found. The results of a recently developed enhanced chemiluminescence immunoassay for measurement of free thyroid hormone are not significantly altered by serum albumin concentration [12]. Thus, more accurate determination of free thyroid hormone can be obtained with this assay in patients with ESRD.
In the present study, pituitarythyroid function was found to be impaired in haemodialysed patients compared with undialysed patients. Although serum concentrations of free T3 and TSH were the same for the most part, serum free T4 concentration measured by enhanced chemiluminescence immunoassay was less in haemodialysed patients than in undialysed patients. This finding agrees with those of a previous report [14].
Production of T4 in the thyroid gland is modulated by TSH in the pituitary, and subsequently converted to T3 in peripheral tissue such as kidney and liver. T3 produced locally by the monodeiodination of T4 at the level of the pituitary inhibits the secretion of TSH in accordance with a negative feedback regulatory mechanism [21]. The serum free T4 concentration in haemodialysed patients was lower than in undialysed patients while comparative serum concentrations of free T3 and TSH were found, possibly due to disturbance of thyroid gland function itself or impaired secretion of TSH from the pituitary.
The serum TSH concentration in haemodialysed patients was within the normal range, as also noted in other studies [5,6,18,19]. A normal baseline serum TSH concentration under a condition of relatively lower serum free T4 concentration may possibly be an indication of impaired secretion of TSH. The response of serum TSH concentration to TRH injection in haemodialysed patients was the same as in undialysed patients, and the relatively lower serum free T4 concentration in haemodialysed patients may thus not be due to impaired response of TSH to TRH. TSH response to TRH in haemodialysed and undialysed patients was significantly less than in normal subjects in other studies [11,15,18] and, consequently, the present results would not be an indication that the response of TSH to TRH is normal in haemodialysed patients.
The serum TSH concentration fluctuates throughout the day, and a nocturnal TSH surge is essential to thyroid function regulation [22]. Wheatley et al. [5] and Bartalena et al. [19] noted the absence of a nocturnal TSH surge in patients on regular maintenance HD. This deficiency during the night may at least partially contribute to low serum free T4 in haemodialysed patients.
The circadian rhythm of blood pressure is attenuated in hypertensive patients with ESRD [2325]. Twenty-four hour blood pressure values were highest during the day and lowest during the night in patients with essential hypertension without renal failure, whereas reduction in blood pressure during the night was less in hypertensive patients with ESRD whether they were haemodialysed or undialysed. The circadian rhythm of plasma atrial natriuretic peptide (ANP) concentration [25] and prolactin concentration [26] diminishes in patients with ESRD. These and the present results suggest that the circadian rhythm of blood pressure and hormonal secretion may be attenuated in patients with ESRD, although the pathogenesis involved has yet to be determined.
The cause of impaired production of TSH remains to be clarified. Tsigos et al. found that the subcutaneous administration of interleukin-6 (IL-6) inhibited the release of TSH and stimulated that of other pituitary hormones including adrenocorticotropic hormone, growth hormone and prolactin in healthy volunteers [27]. Serum IL-6 concentration is elevated in haemodialysed patients beyond that in normal subjects or undialysed patients [2830]. Elevated serum IL-6 concentration may thus possibly be responsible for the deficient nocturnal surge of TSH in haemodialysed patients. The effects of IL-6 on circadian variation in serum TSH concentration in haemodialysed patients should be clarified.
In conclusion, low serum free T4 and a deficient nocturnal surge of TSH were observed in haemodialysed patients but not in undialysed patients, suggesting a deficient nocturnal surge of TSH to be important in impaired thyroid function.
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Acknowledgments
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This work was supported in part by grants from the Erythropoietin Research Fund in Japan.
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Notes
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Correspondence and offprint requests to: Katsuhiko Yonemura MD, PhD, Hemodialysis Unit, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu, 431-3192, Japan. 
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Received for publication: 8. 2.99
Revision received 13.11.99.