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The free T3 index in familial TBG deficiency
~‘lrirrw Chrnur~u Am. I IX ( 1982) I2 I - 123 Elwvier Biomedical Press
CCA
121
1985
Short communication
The free T3 index in familial TBG deficiency R.J. Farrell a, M.J. Duffy a.*, G.J. Duffy ‘, F. Callan’ and T.J. McKenna b “ Drjxutww?~r of Nuclecrr Medru~w md ’ Dqurtnwnt /I/ Ftdo~nnolo~~~. St. V/nw~~r’\ Flovpltul. Du/I//,I 4 (Reprhlic~ (I/ lrrlund) (Received
April 24th. 1981)
Introduction
Although patients with thyroxine-binding-globulin (TBG) deficiency are generally euthyroid, cases of hypothyroidism [I] and thyrotoxicosis [2] have been described. On the other hand, some euthyroid, TBG-deficient subjects have been treated inappropriately for hypothyroidism. It is thus important that accurate tests of thyroid function in TBG-deficient subjects be identified. Since total thyroxine (T4) is usually low in these subjects, the use of the free thyroxine index (FT41) should theoretically compensate for the variation in binding protein levels. However, the FT41 can give rise to misleading results [3]. Serum free T4 (FT4), as measured by equilibrium dialysis, may be normal, decreased [4] or even elevated [5] in euthyroid TBG-deficient subjects. When determined by a kinetic method FT4 was reported to be normal in four subjects with TBG deficiency [3]. In this paper we report the results of thyroid function tests performed on seven subjects, all blood relatives, with familial TBG deficiency. Materials and methods Subjects were interviewed and examined by two clinicians (F.C. and T.J. McK.) for symptoms and signs of thyroid dysfunction. All seven were clinically euthyroid, although three had large goitres. TBG was measured by radioimmunoassay using a commercial kit (Hoechst, Marburg, FRG). Commercial kits were also used for the assay of serum TSH (Becton Dickinson, Orangeburg, NY, USA), T4 (Corning Medical, Halstead, UK) and T3 (Radiochemical Center, Amersham, UK). FT 4 was measured by the Corning “Immophase” method, in which FT4 is determined from its rate of binding to an immobilized antibody. FT4 was calculated using the modified formula of Ekins [6]. T3RUR was measured by the “T3-Res-o-Mat” technique (Mallinckrodt Nuclear, Hazelwood, MO, USA). Free T4 and free T3 indices (FT41 and FT31) were
* To whom correspondence 0009-898
I /82/ooOO-0000/$02.75
should
be addressed ‘C I982 Elacvier Biomedical
Press
122
calculated FT4
1
as follows:
serum 7-4.
=
’
T3RUR
FT31 =
serum T3 T3RUR
Results All seven patients were clinically euthyroid. Serum TSH was normal in the entire family (including the seven TBG-deficient members), thus excluding primary hypothyroidism. Serum T4 was low in all seven subjects (see Table I). Serum FT4 was low in four and normal in three. Five patients had a low FT41; of the remaining two, one was normal and the other borderline low. However, serum T3 was low in only two patients and the free T3 index was normal in all seven. Discussion The accurate determination of thyroid status in patients with abnormal protein binding presents special problems in the laboratory. Although all of the subjects in this study were clinically euthyroid, with the exception of FT31 all the thyroid hormone measurements gave low values in at least some patients (Table I). However, normal serum TSH in these patients excludes primary hypothyroidism. The TSH response to TRH was normal in all but the three goitrous patients, in whom a blunted response is not unexpected [7]. In the seven subjects reported here the FT31 gave the more reliable measure of thyroid status. This index is derived from two well-established thyroid function tests and gives results that correlate with absolute FT3 levels [8]. The FT31 appears to be superior to serum TT4, FT41, total T3 levels and the TRH stimulation in the diagnosis of hyperthyroidism [9,10]. It is also less affected than total T3 by the
TABLE DATA No.
I FROM Sex
PATIENTS
WITH
TBG
DEFICIENCY
TBG
Total T4
Free T4
Free T4
Total T3
Free T3
(mg/l)
(nmol/l)
(pmol/I)
index
(nmol/l)
index
I *
F
3.5
13
5.6
22
1.15
I .Y5
2*
F
9.7
25
7.3
33
2.05
2.7
3”
F
6.5
31
12.6
52
F
8.2
58
IX.5
84
I .66 I .6
2.34
4 5
M
I .o
2x
16.5
56
I.6
3.2
6
M
2.0
33
16.6
59
I.5
2.68
7
M
1.2
20
5.0
3x
I .0x
2.04
5% I66
I 23-3.0x
1.32-3.54
Normal
range
* Patients
I I .o-30.4
5Y- 154
I, 2 and 3 have goitrea.
13.2-32.X
2.32
123
increases in binding proteins associated with pregnancy [ 11,121 and oral contraceptives [8,12]. Our results suggest that the FT31 also has advantages when TBG levels are abnormally low. We conclude that this index deserves further evaluation as a routine thyroid function test especially when high and low TBG levels exist. References 1 Sakurada T, Yamaguchi T, Yoshida K. Yamamoto M, Onodera S, Saito S. Kinetics of thyroxine and triiodothyronine in a case of thyroxine-binding globulin deficiency with hypothyroidism. Tohoku J Exp Med 1974; 612: 133-140. 2 Wahner HW. Emslander RF. Gorman CA. Thyroid overactivity and TBG deficiency simulating ‘T3 hyperthyroidism’. J Clin Endocrinol Metab 197 1; 33: 93-97. 3 Cusick CF. Thyroid function tests in thyroxine-binding globulin deficiency. Clin Biochem 1979; 16: 3133314. 4 Hennemann G. Dotter R, Dolman A. Relationship between total thyroxine and absolute free thyroxine and the influence. of absolute free thyroxine on thyroxine disposal in humans. J Clin Endocrinol Metab I97 I ; 33: 63-67. 5 Premachandra BN. Gossain VV, Perlstein IB. Increased free thyroxine in a euthyroid patient with thyroxine-binding globulin deficiency. J Clin Endocrinol Metab 1976; 42: 309-3 18. 6 Ekins R. Commercial radioimmunoassay for free thyroxine. Lancet 1979; i: 1173. 7 Utiger RD. Tests of the hypothalamic-pituitary-thyroid axis. In: Werner SG, Ingbar SH. eda. The thyroid, a fundamental and clinical test. New York: Harper and Row, 1978: 367-374. 8 Sawin CT. Chopra D. Albano J. Azizi F. The free triiodothyroxinc (T3) index. Ann Intern Med 197X: xx; 474-477. 9 Kallner G, Kagedal B, LJunggren JG, Tryselius M. Clinical value of total T4 and T3 determinations in patients with suspect hyperthyroidism before and after correction for binding proteins. Acta Mcd Stand 1978: 204: 369-373. IO Wiener JD. Value of the free triiodothyroxine index in the diagnosis of hyperthyroidism. Eur J Nucl Med 1980; 5: 119-124. I I Parslow ME, Oddie TH, Fisher DA. Evaluation of serum triiodothyroxine and adjusted triiodothyroxine (free triiodothyroxine index) in pregnancy. Clin Chem 1977; 23: 490-492. I2 Stcpanas AV, Mashiter G. Maisey MN. Serum triiodothyroxine: clinical experience with a new radioimmunoassay kit. Clin Endocrinol 1977; 6: 171-l X3.
CCA
121
1985
Short communication
The free T3 index in familial TBG deficiency R.J. Farrell a, M.J. Duffy a.*, G.J. Duffy ‘, F. Callan’ and T.J. McKenna b “ Drjxutww?~r of Nuclecrr Medru~w md ’ Dqurtnwnt /I/ Ftdo~nnolo~~~. St. V/nw~~r’\ Flovpltul. Du/I//,I 4 (Reprhlic~ (I/ lrrlund) (Received
April 24th. 1981)
Introduction
Although patients with thyroxine-binding-globulin (TBG) deficiency are generally euthyroid, cases of hypothyroidism [I] and thyrotoxicosis [2] have been described. On the other hand, some euthyroid, TBG-deficient subjects have been treated inappropriately for hypothyroidism. It is thus important that accurate tests of thyroid function in TBG-deficient subjects be identified. Since total thyroxine (T4) is usually low in these subjects, the use of the free thyroxine index (FT41) should theoretically compensate for the variation in binding protein levels. However, the FT41 can give rise to misleading results [3]. Serum free T4 (FT4), as measured by equilibrium dialysis, may be normal, decreased [4] or even elevated [5] in euthyroid TBG-deficient subjects. When determined by a kinetic method FT4 was reported to be normal in four subjects with TBG deficiency [3]. In this paper we report the results of thyroid function tests performed on seven subjects, all blood relatives, with familial TBG deficiency. Materials and methods Subjects were interviewed and examined by two clinicians (F.C. and T.J. McK.) for symptoms and signs of thyroid dysfunction. All seven were clinically euthyroid, although three had large goitres. TBG was measured by radioimmunoassay using a commercial kit (Hoechst, Marburg, FRG). Commercial kits were also used for the assay of serum TSH (Becton Dickinson, Orangeburg, NY, USA), T4 (Corning Medical, Halstead, UK) and T3 (Radiochemical Center, Amersham, UK). FT 4 was measured by the Corning “Immophase” method, in which FT4 is determined from its rate of binding to an immobilized antibody. FT4 was calculated using the modified formula of Ekins [6]. T3RUR was measured by the “T3-Res-o-Mat” technique (Mallinckrodt Nuclear, Hazelwood, MO, USA). Free T4 and free T3 indices (FT41 and FT31) were
* To whom correspondence 0009-898
I /82/ooOO-0000/$02.75
should
be addressed ‘C I982 Elacvier Biomedical
Press
122
calculated FT4
1
as follows:
serum 7-4.
=
’
T3RUR
FT31 =
serum T3 T3RUR
Results All seven patients were clinically euthyroid. Serum TSH was normal in the entire family (including the seven TBG-deficient members), thus excluding primary hypothyroidism. Serum T4 was low in all seven subjects (see Table I). Serum FT4 was low in four and normal in three. Five patients had a low FT41; of the remaining two, one was normal and the other borderline low. However, serum T3 was low in only two patients and the free T3 index was normal in all seven. Discussion The accurate determination of thyroid status in patients with abnormal protein binding presents special problems in the laboratory. Although all of the subjects in this study were clinically euthyroid, with the exception of FT31 all the thyroid hormone measurements gave low values in at least some patients (Table I). However, normal serum TSH in these patients excludes primary hypothyroidism. The TSH response to TRH was normal in all but the three goitrous patients, in whom a blunted response is not unexpected [7]. In the seven subjects reported here the FT31 gave the more reliable measure of thyroid status. This index is derived from two well-established thyroid function tests and gives results that correlate with absolute FT3 levels [8]. The FT31 appears to be superior to serum TT4, FT41, total T3 levels and the TRH stimulation in the diagnosis of hyperthyroidism [9,10]. It is also less affected than total T3 by the
TABLE DATA No.
I FROM Sex
PATIENTS
WITH
TBG
DEFICIENCY
TBG
Total T4
Free T4
Free T4
Total T3
Free T3
(mg/l)
(nmol/l)
(pmol/I)
index
(nmol/l)
index
I *
F
3.5
13
5.6
22
1.15
I .Y5
2*
F
9.7
25
7.3
33
2.05
2.7
3”
F
6.5
31
12.6
52
F
8.2
58
IX.5
84
I .66 I .6
2.34
4 5
M
I .o
2x
16.5
56
I.6
3.2
6
M
2.0
33
16.6
59
I.5
2.68
7
M
1.2
20
5.0
3x
I .0x
2.04
5% I66
I 23-3.0x
1.32-3.54
Normal
range
* Patients
I I .o-30.4
5Y- 154
I, 2 and 3 have goitrea.
13.2-32.X
2.32
123
increases in binding proteins associated with pregnancy [ 11,121 and oral contraceptives [8,12]. Our results suggest that the FT31 also has advantages when TBG levels are abnormally low. We conclude that this index deserves further evaluation as a routine thyroid function test especially when high and low TBG levels exist. References 1 Sakurada T, Yamaguchi T, Yoshida K. Yamamoto M, Onodera S, Saito S. Kinetics of thyroxine and triiodothyronine in a case of thyroxine-binding globulin deficiency with hypothyroidism. Tohoku J Exp Med 1974; 612: 133-140. 2 Wahner HW. Emslander RF. Gorman CA. Thyroid overactivity and TBG deficiency simulating ‘T3 hyperthyroidism’. J Clin Endocrinol Metab 197 1; 33: 93-97. 3 Cusick CF. Thyroid function tests in thyroxine-binding globulin deficiency. Clin Biochem 1979; 16: 3133314. 4 Hennemann G. Dotter R, Dolman A. Relationship between total thyroxine and absolute free thyroxine and the influence. of absolute free thyroxine on thyroxine disposal in humans. J Clin Endocrinol Metab I97 I ; 33: 63-67. 5 Premachandra BN. Gossain VV, Perlstein IB. Increased free thyroxine in a euthyroid patient with thyroxine-binding globulin deficiency. J Clin Endocrinol Metab 1976; 42: 309-3 18. 6 Ekins R. Commercial radioimmunoassay for free thyroxine. Lancet 1979; i: 1173. 7 Utiger RD. Tests of the hypothalamic-pituitary-thyroid axis. In: Werner SG, Ingbar SH. eda. The thyroid, a fundamental and clinical test. New York: Harper and Row, 1978: 367-374. 8 Sawin CT. Chopra D. Albano J. Azizi F. The free triiodothyroxinc (T3) index. Ann Intern Med 197X: xx; 474-477. 9 Kallner G, Kagedal B, LJunggren JG, Tryselius M. Clinical value of total T4 and T3 determinations in patients with suspect hyperthyroidism before and after correction for binding proteins. Acta Mcd Stand 1978: 204: 369-373. IO Wiener JD. Value of the free triiodothyroxine index in the diagnosis of hyperthyroidism. Eur J Nucl Med 1980; 5: 119-124. I I Parslow ME, Oddie TH, Fisher DA. Evaluation of serum triiodothyroxine and adjusted triiodothyroxine (free triiodothyroxine index) in pregnancy. Clin Chem 1977; 23: 490-492. I2 Stcpanas AV, Mashiter G. Maisey MN. Serum triiodothyroxine: clinical experience with a new radioimmunoassay kit. Clin Endocrinol 1977; 6: 171-l X3.