Ratio of Serum Free Triiodothyronine to Free Thyroxine in Graves Hyperthyroidism and Thyrotoxicosis Caused by Painless Thyroiditis

Endocrine Journal 2005, 52 (5), 537 542 Ratio of Serum Free Triiodothyronine to Free Thyroxine in Graves Hyperthyroidism and Thyrotoxicosis Caused by Painless Thyroiditis JAEDUK YOSHIMURA NOH, NAOKO MOMOTANI*, SHUJI FUKADA**, KOICHI ITO, AKIRA MIYAUCHI** AND NOBUYUKI AMINO** Ito Hospital, 4-3-6, Jingumae, Shibuya-ku, Tokyo 150-8308, Japan *Hokenkaikan Clinic, 1-2, Shinjuku-ku, Ichigaya Sadohara-cho, Tokyo 162-0842, Japan **Kuma Hospital, 8-2-35 Shimoyamate-dori, Chuo-ku, Kobe 650-0011, Japan Abstract. The serum T 3 to T 4 ratio is a useful indicator for differentiating destruction-induced thyrotoxicosis from Graves thyrotoxicosis. However, the usefulness of the serum free T 3 (FT 3 ) to free T 4 (FT 4 ) ratio is controversial. We therefore systematically evaluated the usefulness of this ratio, based on measurements made using two widely available commercial kits in two hospitals. Eighty-two untreated patients with thyrotoxicosis (48 patients with Graves disease and 34 patients with painless thyroiditis) were examined in Kuma Hospital, and 218 patients (126 with Graves disease and 92 with painless thyroiditis) and 66 normal controls were examined in Ito Hospital. The FT 3 and FT 4 values, as well as the FT 3 / FT 4 ratios, were significantly higher in the patients with Graves disease than in those with painless thyroiditis in both hospitals, but considerable overlap between the two disorders was observed. Receiver operating characteristic (ROC) curves for the FT 3 and FT 4 values and the FT 3 /FT 4 ratios of patients with Graves disease and those with painless thyroiditis seen in both hospitals were prepared, and the area under the curves (AUC), the cut-off points for discriminating Graves disease from painless thyroiditis, the sensitivity, and the specificity were calculated. AUC and sensitivity of the FT 3 /FT 4 ratio were smaller than those of FT 3 and FT 4 in both hospitals. The patients treated at Ito hospital were then divided into 4 groups according to their FT 4 levels (A: 2.3, B: >2.3~ 3.9, C: 3.9~ 5.4, D: >5.4 ng/dl), and the AUC, cutoff points, sensitivity, and specificity of the FT 3 /FT 4 ratios were calculated. The AUC and sensitivity of each group increased with the FT 4 levels (AUC: 57.8%, 72.1%, 91.1%, and 93.4%, respectively; sensitivity: 62.6%, 50.0%, 77.8%, and 97.0%, respectively). The means ± SE of the FT 3 /FT 4 ratio in the Graves disease groups were 3.1 ± 0.22, 3.1 ± 0.09, 3.2 ± 0.06, and 3.1 ± 0.07, respectively, versus 2.9 ± 0.1, 2.6 ± 0.07, 2.5 ± 0.12, and 2.3 ± 0.15, respectively, in the painless thyroiditis groups. In the painless thyroiditis patients, the difference in the FT 3 /FT 4 ratio between group A and group D was significant (p<0.05). Thus, the FT 3 /FT 4 ratio in patients with Graves disease likely remains unchanged as the FT 4 level rises, whereas this ratio decreases as the FT 4 level rises in patients with painless thyroiditis. In conclusion, the FT 3 /FT 4 ratios of patients with painless thyroiditis overlapped with those of patients with Graves disease. However, this ratio was useful for differentiating between these two disorders when the FT 4 values were high. Key words: FT 3 /FT 4 ratio, Thyrotoxicosis, Graves disease, Painless thyroiditis (Endocrine Journal 52: 537 542, 2005) DESTRUCTION-induced thyrotoxicosis is often observed in patients with painless thyroiditis, postpartum thyroiditis, and subacute thyroiditis [1], and it is important to differentiate this type of thyrotoxicosis from Received: September 8, 2004 Accepted: June 13, 2005 Correspondence to: Dr. Jaeduk YOSHIMURA NOH, Ito Hospital, 4-3-6, Jingumae, Shibuya-ku, Tokyo 150-8308, Japan the stimulation-induced thyrotoxicosis seen in patients with Graves disease because patients with Graves disease must be treated with antithyroid drugs, radioisotope therapy, or a subtotal thyroidectomy, whereas patients with destruction-induced thyrotoxicosis can be managed conservatively. Typical cases of subacute thyroiditis are relatively easy to diagnose, but it is often difficult to differentiate painless thyroiditis from Graves thyrotoxicosis without measuring radioactive

538 YOSHIMURA NOH et al. iodine uptake (RAIU). Thyrotoxicosis developing early during the postpartum period is usually destructioninduced thyrotoxicosis, but Graves thyrotoxicosis sometimes develops 3 to 6 months postpartum [2]; differentiating between these two conditions is difficult because the RAIU test is contraindicated in lactating patients. Another problem with measuring RAIU is that not all clinics are equipped to perform this test, and in Japan, patients must be kept on a low iodine diet for 2 weeks before undergoing RAIU. Thus, it is not practical to use the RAIU test to differentiate between these two conditions in all patients with thyrotoxicosis. The detection of anti-tsh receptor antibodies (TBII) is generally a useful means of diagnosing Graves thyrotoxicosis, though 10 30% of patients with this disease are negative for TBII when tested using a conventional radioreceptor assay [3 5] and 15% of patients with painless thyroiditis are reportedly positive [6]. Thus, TBII is not a reliable marker for differentiating between the two types of thyrotoxicosis. The serum T 3 to T 4 ratio has previously been reported to be helpful in differentiating destruction-induced thyrotoxicosis from Graves thyrotoxicosis [1, 7]. The measurement of FT 4 and FT 3, instead of total T 4 and T 3, was recently introduced, but Shigemasa et al. [8] found that the FT 3 to FT 4 ratio was not useful for differentiating between the two types of thyrotoxicosis. More recently, Izumi et al. [9] reported that the FT 3 to FT 4 ratio facilitates a differentiated diagnosis when a sophisticated assay system, unaffected by the concentration of thyroxine binding proteins, is employed. In this study, we systematically evaluated the usefulness of the FT 3 to FT 4 ratio in making a differential diagnosis by using widely available commercial kits to measure serum FT 3 and FT 4 levels. Patients Patients and Methods Graves disease was diagnosed on the basis of clinical findings and laboratory tests showing high FT 4 and FT 3 levels, low TSH, increased TBII activity, and a high RAIU. Functioning tumors were excluded by confirming the diffuse uptake of radioactive iodine. Painless thyroiditis was diagnosed on the basis of increased FT 4 and FT 3 values and a low RAIU. Postpartum painless thyroiditis cases were not included in this study, and the cause of the painless thyroiditis was unknown. Subacute thyroiditis was excluded based on the identification of a painful goiter. All serum samples were obtained during the thyrotoxic phase before treatment. At Kuma Hospital, 54 patients with untreated Graves hyperthyroidism, 48 of whom had FT 4 and FT 3 values below the upper detection limit (FT3 <30.0 pg/ml, FT4 <6.0 ng/dl) (41 women, 7 men; age, 38.6 ± 15.5 years), and 34 patients with painless thyroiditis (28 women, 6 men; age, 35.3 ± 14.2 years) were examined. No significant differences in sex or age distribution were observed between these two groups. At Ito Hospital, 138 patients with untreated Graves hyperthyroidism, 126 of whom had FT 4 and FT 3 values below the upper detection limit (FT3 <30.0 pg/ml, FT4 <10.0 ng/dl) (107 women, 19 men; age, 45.2 ± 14.6 years), and 92 patients with untreated painless thyroiditis (82 women, 10 men; age, 43.9 ± 14.2 years) were examined. Control samples were obtained from 66 normal individuals (55 women, 11 men; age, 33.7 ± 16.2 years). No significant differences in the sex distributions of the 3 groups or in the ages of the Graves hyperthyroidism group and the painless thyroiditis group were observed. Informed consent was obtained from all participants. Detection of serum FT 4 and FT 3 levels At Kuma Hospital, serum FT 4 and FT 3 values were measured using Architect FT 3 and FT 4 commercial kits (Abbott Japan Diagnostics, Tokyo, Japan); the reference ranges were 1.7 3.7 pg/ml and 0.7 1.6 ng/dl, respectively. At Ito Hospital, the serum FT 4 and FT 3 values were measured using Lumipulse FT 3 and FT 4 commercial kits (Fujirebio Inc., Tokyo, Japan); the reference ranges were 2.5 4.5 pg/ml and 0.75 1.75 ng/dl, respectively, with an upper detection limit of 30.0 pg/ml for FT 3 and 10.0 ng/dl for FT 4. Statistical methods The FT 3 /FT 4 ratios were compared between the two groups using the Mann-Whitney U test and the Tukey- Kramer HSD test. A Spearman rank correlation was employed for simple correlation analysis. Differences were considered significant at p <0.05. Cut-off values were calculated using receiver operating characteristics (ROC) curves.

SIGNIFICANCE OF FT 3 TO FT 4 RATIO 539 Results The individual serum FT 3 /FT 4 ratio values in the patients with Graves disease and those with painless thyroiditis at Kuma and Ito Hospitals are shown in Fig. 1. Significant differences between the Graves disease and painless thyroiditis groups were observed, but the values in the Graves disease group overlapped considerably with those in the painless thyroiditis group. The FT 3 and FT 4 values and the FT 3 /FT 4 ratios of the patients with Graves disease and painless thyroiditis who were treated at Kuma and Ito Hospitals are presented in Table 1. At both hospitals, the FT 3 and FT 4 values and the FT 3 /FT 4 ratios of the thyrotoxic patients with Graves disease were higher than those of patients with painless thyroiditis (P<0.001). The ROC curves for the FT 3 and FT 4 values and the FT 3 / FT 4 ratios of patients with Graves disease and painless thyroiditis treated in both hospitals were plotted, and the area under the curves (AUC), the cut-off points for discriminating Graves disease from painless thyroiditis, the sensitivity, and the specificity were calculated (Table 2). The AUC and sensitivity values were smaller for the FT 3 /FT 4 ratio than for the FT 3 and FT 4 levels in both hospitals. No correlations between the FT 3 /FT 4 ratio and radioactive iodine uptake in either the patients with Graves disease or those with painless thyroiditis were observed among the patients treated at Ito Hospital. The patients at Ito Hospital were then divided into 4 groups according to their FT 4 levels : group A: 2.3, group B: 2.3~ 3.9, group C: 3.9~ 5.4, and group D: >5.4 ng/dl. The AUC, cut-off points for discriminating patients with Graves disease from those with painless thyroiditis, the sensitivity, and the specificity of the FT 3 /FT 4 ratios were calculated (Table 3). The individual serum FT 3 /FT 4 ratios are shown in Fig. 2. No significant difference in age or sex were observed among the 4 groups of patients with Graves disease, but group C was significantly older than the other Table 2. Differentiation of Graves disease from painless thyroiditis Fig. 1. Individual serum FT 4 /FT 3 ratios in Graves disease, painless thyroiditis, and in normal controls. AUC (%) Cutoff point Sensitivity (%) Specificity (%) Kuma Hospital FT 3 (pg/ml) 84.3 6.5 91.7 67.6 FT 4 (ng/dl) 83.8 2.5 91.7 73.5 FT 3 /FT 4 ratio 71.0 2.8 77.1 58.8 Ito Hospital FT 3 (pg/ml) 84.5 10.5 77.8 82.6 FT 4 (ng/dl) 78.8 3.3 77.8 71.7 FT 3 /FT 4 ratio 75.3 3.0 61.9 80.4 AUC: Area under the curve Table 1. FT 3 and FT 4 values and FT 3 /FT 4 ratios of Graves disease patients and painless thyroiditis patients at Kuma Hospital and Ito Hospital. FT 3 (pg/ml) FT 4 (ng/dl) FT 3 /FT 4 Median range Median range Median range Kuma Hospital Graves disease (n = 48) 11.5 3.2 28.0* 3.4 1.4 5.7* 3.4 2.3 5.8* Painless thyroiditis (n = 34) 4.9 2.6 17.4 2.1 0.8 4.2 2.7 1.4 5.5 Ito Hospital Graves disease (n = 126) 13.3 3.6 29.5* 4.4 1.4 9.6* 3.1 2.2 4.3* Painless thyroiditis (n = 92) 6.9 4.0 24.5 2.5 1.4 8.4 2.6 1.7 5.1 Normal control (n = 66) 3.2 2.4 4.5 1.1 0.8 1.6 2.9 2.0 4.2 ( ): number of patients * Significant difference from the value in the painless thyroiditis group and normal control group at P<0.001.

540 YOSHIMURA NOH et al. Table 3. Differentiation of Graves disease from painless thyroiditis in Ito Hospital according to the FT 4 levels FT 4 (ng/dl) Graves/PT AUC (%) Cutoff point of FT 3 /FT 4 sensitivity (%) specificity (%) 2.3 8/37 57.8 2.8 62.5 59.5 >2.3~ 3.9 40/38 72.1 3.0 55.0 86.8 3.9~ 5.4 45/9 91.1 2.8 77.8 88.9 >5.4 33/8 93.6 2.4 97.0 75.0 Graves/PT: Number of patients with Graves disease/number of patients with painless thyroiditis AUC: Area under the curve Fig. 2. Individual serum FT 4 /FT 3 ratios of groups, A, B, C, and D with Graves disease and painless thyroiditis. The patients at Ito Hospital were divided into 4 groups according to their FT 4 levels: group A, 2.3; group B, 2.3~ 3.9; group C, 3.9~ 5.4; and group D, >5.4 ng/dl. range of the FT 3 /FT 4 ratio at 1 day, 2 30 days, 31 90 days, 91 180 days, 181 360 days, and >360 days after the initial diagnosis were calculated in each of the painless thyroiditis groups (Table 4). The values at 31 90 days after the initial diagnosis were the highest in all groups, and the degree of elevation corresponded to the FT 4 level at the time of the initial diagnosis. The median and range of the FT 4 levels at 31 90 days after diagnosis in each of the painless thyroiditis groups were 0.97 ng/dl (0.25 2.4), 0.84 ng/dl (0.15 3.24), 0.78 ng/dl (0.17 2.81), and 0.62 ng/dl (0.34 1.42), respectively. Those of TSH at 31 90 days after diagnosis were 1.67 U/ml (0.01 71.1), 3.66 U/ml (0.01 94.9), 3.81 U/ml (0.01 45.3), and 20.2 U/ml (6.8 43.9), respectively. groups among the patients with painless thyroiditis (p<0.05). The FT 3 /FT 4 ratios were significantly higher in groups B, C and D with Graves disease than in the corresponding groups with painless thyroiditis. The AUC and sensitivity of each group increased as the FT 4 levels rose. The mean ± SE of the FT 3 /FT 4 ratios in the Graves disease groups were 3.1 ± 0.22, 3.1 ± 0.09, 3.2 ± 0.06, and 3.1 ± 0.07, respectively, versus 2.9 ± 0.1, 2.6 ± 0.07, 2.5 ± 0.12, and 2.3 ± 0.15, respectively, in the painless thyroiditis groups, and the difference in the FT 3 /FT 4 ratios of groups A and D with painless thyroiditis was significant (p<0.05). The median and Discussion Thyrotoxicosis in patients with painless thyroiditis and subacute thyroiditis is caused by thyroid destruction, and painless thyroiditis has been reported to account for 0 23% of all thyrotoxicosis cases [10 12]. Painless thyroiditis during the postpartum period, socalled postpartum thyroiditis, is 10 times more common in the general population than postpartum Graves disease [13]. The thyrotoxic symptoms in painless thyroiditis are usually milder than those associated with Graves disease, and as a result, many cases may be Table 4. FT 3 /FT 4 ratios at different time points after initial diagnosis in each of the painless thyroiditis groups 1 day 2 30 days 31 90 days 91 180 days 181 360 days >360 days Group A 2.72 (2.27 4.24) 2.77 (2.24 3.59) 3.16 (2.14 8.0)* 2.97 (2.12 3.81) 2.82 (2.09 7.89) 3.00 (2.38 3.49) Group B 2.64 (1.74 3.79) 2.69 (2.05 5.88) 3.55 (2.04 9.69)* 3.40 (2.18 7.05)* 3.04 (2.18 7.05) 3.00 (2.56 5.07) Group C 2.49 (1.81 3.01) 3.42 (2.73 3.82) 3.58 (2.67 9.41)* 3.22 (2.79 4.35) 2.87 (2.11 3.07) 2.99 (1.95 3.07) Group D 2.32 (1.70 2.93) 2.86 (2.41 3.33) 4.49 (2.46 5.22)* 3.25 (2.75 3.75) 2.98 (2.73 3.02) 2.88 (2.74 3.03) All values are for the Median (Range). * P<0.05 compared with value for 1 day.

SIGNIFICANCE OF FT 3 TO FT 4 RATIO 541 missed. Because the symptoms are mild and nonspecific, most patients with painless thyroiditis probably consult a general practitioner, rather than a specialized endocrinology clinic. The prevalence of painless thyroiditis is thus probably higher than recognized. Destruction-induced thyrotoxicosis can be definitively differentiated from Graves disease using the RAIU test; however, this test is not available in the offices of general practitioners or in most clinics and it is contraindicated in lactating women. Thus, there has long been a need for a simple, practical test to differentiate between these two disorders. The zinc concentration in erythrocytes has recently been reported to be a useful measure for making a differential diagnosis [4], but such measurements are not routinely performed. A highly sensitive thirdgeneration TSH assay has also been reported to be useful [14], but a clear overlap in values for the two types of thyrotoxicosis limits its practical use. A T 3 /T 4 ratio (ng/ g) of less than 20 has been reported to indicate destruction-induced thyrotoxicosis [1, 7]. However, this ratio is affected by the thyroxinebinding globulin (TBG) concentration [15]. Several FT 4 and FT 3 assays have recently been introduced, and most of these assays are unaffected by the TBG concentration. Izumi et al. reported that the FT 3 /FT 4 ratio was useful for differentiating between the two types of thyrotoxicosis, although some overlap between the values for Graves hyperthyroidism and destructioninduced thyrotoxicosis was observed [9]. In that study, FT 4 was measured using their analogue method and FT 3 was measured using a radioimmunoassay with a 125 I-labeled anti-t 3 monoclonal antibody. Both of these assays are minimally influenced by binding proteins and autoantibodies to T 4 and T 3. The differences in the assay methods used in this previous study and the present study may account for the difference in the FT 3 /FT 4 ratio results. Which method is more useful for differentiating the two types of thyrotoxicosis? The T 3 /T 4 ratio seems to be more useful than the FT 3 /FT 4 ratio for differentiating Graves disease from painless thyroiditis because 85.5% (71/83) of the thyrotoxic patients with a T 3 /T 4 ratio of >20 had Graves disease [16]. Moreover, the upper detection limit for FT 3 and FT 4 is a major disadvantage when using the FT 3 /FT 4 ratio to diagnose in patients with severe thyrotoxicosis. In this study, the FT 3 and FT 4 values and the FT 3 /FT 4 ratios of the patients with Graves disease, were higher than those in patients with painless thyroiditis in both hospitals, but considerable overlap was noted. An analysis of the AUCs, the cut-off points for discriminating patients with Graves disease from those with painless thyroiditis, the sensitivity, and the specificity revealed that the FT 3 /FT 4 ratio was no more useful as an indicator for the differential diagnosis of Graves disease from painless thyroiditis than the FT 3 and FT 4 values. We next divided the patients treated at Ito Hospital into 4 groups according to their FT 4 levels, and the AUCs, cut-off points, sensitivity, and specificity of the FT 3 /FT 4 ratios for each group were calculated. Both the AUC and the sensitivity values increased with increasing FT 4 levels in all groups, suggesting that the FT 3 /FT 4 ratio may be useful for diagnosing patients with high FT 4 levels. No significant differences between the FT 3 /FT 4 ratios of the 4 Graves disease groups were observed, but the ratios in the painless thyroiditis groups decreased as the FT 4 levels increased. Type I and type II iodothyronine deiodinases are present in the thyroid [17, 18]. Type I iodothyronine deiodinase is increased by thyroid hormone, and Type II iodothyronine deiodinase is regulated by TSH receptors [17]. In painless thyroiditis, the FT 4 levels depend on the degree of thyroid destruction, and the activities of both deiodinases may also be affected by the degree of thyroid destruction. In patients with painless thyroiditis, the FT 3 /FT 4 ratios and the TSH levels increased over the course of the study, rising steadily during the 31-to-90-day period after the initial diagnosis in all groups. These results raise the possibility that changes in the FT 3 /FT 4 ratio are regulated by both deiodinases in patients with painless thyroiditis. The measurement of TBII is useful for the diagnosis of Graves disease, but some weakly TBII-positive patients with painless thyroiditis have also been observed. The cutoff value for TBII used by the Ito Hospital is 10%, and 13 patients with TBII values between >10 to 20% were included in this study (Graves disease, n = 12; painless thyroiditis, n = 1 patient). The FT 4, FT 3 /FT 4 ratio and TBII values of the patient with painless thyroiditis were 2.33 ng/dl, 2.45, and 15.9%, respectively, and this patient was correctly diagnosed using the cutoff values. Among the patients with Graves disease, 66.7% (8/12) had an FT 3 /FT 4 ratio > the cutoff value, and the FT 3 /FT 4 ratio of all (6/6) the Graves patients in groups C and D exceeded the cutoff value. Therefore, the FT 3 /FT 4 ratio may play a peripheral role for differentiating

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