The Relationship of Thyroid-stimulating Hormone (TSH), Thyroxine (T4), and Triiodothyronine (T3) in Primary Thyroid Failure MANJULA S. KUMAR, PH.D., ALI M. SAFA, M.D., SHARAD D. DEODHAR, M.D., PH.D., AND O. PETER SCHUMACHER, M.D., PH.D.
HUMAN
PITUITARY
thyroid-stimulating
Departments of Immunopathology and Endocrinology, Cleveland Clinic Foundation, Cleveland, Ohio
roidism. 6-8,10 Elevation of TSH is now considered a sine qua non for this diagnosis. 16 It is also appreciated that the level of serum TSH in hypothyroid individuals is a function of serum thyroxine (T4) level. 710 The role of triiodothyronine (T3) in the regulation of thyroid function has generated considerable interest in recent years, 5,911,12,15 but the diagnostic value of serum T3 determinations in hypothyroidism is not clear. The present study was undertaken to assess the relationship between the serum concentrations of TSH, T4, and T3 and effective thyroxine ratio (ETR) in untreated patients with primary thyroid failure, and also to evaluate the diagnostic value of these tests in these patients.
hormone
(TSH) and its responses in disorders of the thyroid gland have been thoroughly studied. 8-8 It is generally accepted that the serum TSH concentrations are almost invariably elevated in patients with primary hypothyReceived September 17, 1976; accepted for publication November 18, 1976. Supported in part by the Carl T. Reinberger Fund. Presented at the Fall Meeting of the American Society of Clinical Pathologists, September 1975. Address reprint requests to Dr. Kumar: Department of Immunopathology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio 44106.
747
Materials and Methods Patients included in this study were evaluated at the Cleveland Clinic between March 1972 and November 1974. Sixty-five patients were clinically hypothyroid; the diagnosis of probable hypothyroidism was considered in the rest of the cases and confirmed by high TSH levels. TSH values of more than 10 /^u/rnl were considered elevated (normal 2.8 ± 1.0). Patients who were partially treated or taking estrogen or oral contraceptives were not included. The age and sex distribution of these patients is summarized in Table 1. The patients were classified into the following categories: 1. Idiopathic hypothyroidism (n =42). These patients had no goiter and the thyroglobulin antibody (TG-AB) titer was negative. 2. Hashimoto's thyroiditis (n = 22). These patients either had positive TG-AB titers greater than
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
Kumar, Manjula S., Safa, Ali M., Deodhar, Sharad D., and Schumacher, O. Peter: The relationship of thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) in primary thyroid failure. Am J Clin Pathol 68:747-751,1977. Thyroid-stimulating hormone (TSH), serum thyroxine (T4) and triiodothyronine (T3) in sera of 100 patients with primary thyroid failure were measured by radioimmunoassay. Effective thyroxine ratio (ETR) was also measured in 69 of these sera. TSH was elevated in all, with a mean of 76.7 ± 55 fiV/m\ (range 11 to 240 ju.U/ml), and was used to confirm the diagnosis. Mean T4 and T3 levels in this group were 1.8 ± 1.5 /u.g/100 ml (range < 0.2 to 7.0 fig/100 ml) and 76.7 ± 76 ng/100 ml (range < 10 to 600 ng/100 ml), respectively. Mean ETR was 0.81 ± 0.05. A moderate inverse relationship was observed between TSH and T4 (r = 0.73), in contrast to TSH and T3 and TSH and ETR, which showed comparatively poor relationships (r = 0.41 and 0.43). This observation, in addition to the finding that 17 patients had subnormal T4 but normal or elevated T3, suggests that normal T3 levels alone may not be sufficient to maintain euthyroidism. In contrast, there were only three clinically hypothyroid patients who had elevated TSH, normal T4, but subnormal T3 levels. This study indicates that T4 and T3 may function together to maintain euthyroidism, and that in addition to serum TSH, T4 determination has more diagnostic value than serum T3 or ETR in these patients. (Key words: Thyroid-stimulating hormone; Triiodothyronine; Radioimmunoassay; Primary thyroid failure; Effective thyroxine ratio.)
748
A.J.C.P. • December 1977
KUMAR ETAL.
10
350 r =0.73
^
250
8
6 O 150 100
£!•.
>j 4 \ 2
-
\ •• • •
80
•• 60
•ay..
•ill"
SUBNORMAL •••1 • • • • •
SUPRANORMAL
FIG. 1. Distribution of serum T4 levels in 100 primary hypothyroid patients. The solid horizontal line indicates the mean normal level, and the dotted lines indicate ±2 SD.
40
20 TSH Normal 0.2
1:2,500 with or without diffuse goiter, or the diagnosis was confirmed histologically by needle biopsy or surgery. A group of patients (n = 25) who had TG-AB titers less than 1:2,500 or negative titers, but had diffuse firm goiters, were classified as probable Hashimoto's thyroiditis. 3. Post mI therapy hypothyroidism (n = 4). These patients received conventional doses of 131I for treatment of hyperthyroidism due to Graves' disease. 4. Post-thyroidectomy hypothyroidism (n = 7). Radioimmunoassay
of TSH, T4 and T3
Serum TSH, T4 and T3 were measured by doubleantibody radioimmunoassay technic. Methods previously described4-5,7 were used, with slight modifications. Human TSH for labeling and rabbit anti-TSH were obtained from the National Institute of Arthritis, MeTable 1. TSH, T4 and T3 Levels in Primary Hypothyroid Patients at Different Ages
Age (Yr.) 1-20 21-40 41-60 61-80 TOTAL
Total No. (Female + Male)
TSH, MU/ml Mean ± SD
9 (6 + 3) 23 (18 + 5) 42 (32 + 10) 26 (18 + 8) 100 (74 + 26)
147.7 ± 70* 75 ± 54 71 ± 53 62 ± 34 76.7 ± 55
* Significantly higher, P =
HUMAN
PITUITARY
thyroid-stimulating
Departments of Immunopathology and Endocrinology, Cleveland Clinic Foundation, Cleveland, Ohio
roidism. 6-8,10 Elevation of TSH is now considered a sine qua non for this diagnosis. 16 It is also appreciated that the level of serum TSH in hypothyroid individuals is a function of serum thyroxine (T4) level. 710 The role of triiodothyronine (T3) in the regulation of thyroid function has generated considerable interest in recent years, 5,911,12,15 but the diagnostic value of serum T3 determinations in hypothyroidism is not clear. The present study was undertaken to assess the relationship between the serum concentrations of TSH, T4, and T3 and effective thyroxine ratio (ETR) in untreated patients with primary thyroid failure, and also to evaluate the diagnostic value of these tests in these patients.
hormone
(TSH) and its responses in disorders of the thyroid gland have been thoroughly studied. 8-8 It is generally accepted that the serum TSH concentrations are almost invariably elevated in patients with primary hypothyReceived September 17, 1976; accepted for publication November 18, 1976. Supported in part by the Carl T. Reinberger Fund. Presented at the Fall Meeting of the American Society of Clinical Pathologists, September 1975. Address reprint requests to Dr. Kumar: Department of Immunopathology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio 44106.
747
Materials and Methods Patients included in this study were evaluated at the Cleveland Clinic between March 1972 and November 1974. Sixty-five patients were clinically hypothyroid; the diagnosis of probable hypothyroidism was considered in the rest of the cases and confirmed by high TSH levels. TSH values of more than 10 /^u/rnl were considered elevated (normal 2.8 ± 1.0). Patients who were partially treated or taking estrogen or oral contraceptives were not included. The age and sex distribution of these patients is summarized in Table 1. The patients were classified into the following categories: 1. Idiopathic hypothyroidism (n =42). These patients had no goiter and the thyroglobulin antibody (TG-AB) titer was negative. 2. Hashimoto's thyroiditis (n = 22). These patients either had positive TG-AB titers greater than
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
Kumar, Manjula S., Safa, Ali M., Deodhar, Sharad D., and Schumacher, O. Peter: The relationship of thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) in primary thyroid failure. Am J Clin Pathol 68:747-751,1977. Thyroid-stimulating hormone (TSH), serum thyroxine (T4) and triiodothyronine (T3) in sera of 100 patients with primary thyroid failure were measured by radioimmunoassay. Effective thyroxine ratio (ETR) was also measured in 69 of these sera. TSH was elevated in all, with a mean of 76.7 ± 55 fiV/m\ (range 11 to 240 ju.U/ml), and was used to confirm the diagnosis. Mean T4 and T3 levels in this group were 1.8 ± 1.5 /u.g/100 ml (range < 0.2 to 7.0 fig/100 ml) and 76.7 ± 76 ng/100 ml (range < 10 to 600 ng/100 ml), respectively. Mean ETR was 0.81 ± 0.05. A moderate inverse relationship was observed between TSH and T4 (r = 0.73), in contrast to TSH and T3 and TSH and ETR, which showed comparatively poor relationships (r = 0.41 and 0.43). This observation, in addition to the finding that 17 patients had subnormal T4 but normal or elevated T3, suggests that normal T3 levels alone may not be sufficient to maintain euthyroidism. In contrast, there were only three clinically hypothyroid patients who had elevated TSH, normal T4, but subnormal T3 levels. This study indicates that T4 and T3 may function together to maintain euthyroidism, and that in addition to serum TSH, T4 determination has more diagnostic value than serum T3 or ETR in these patients. (Key words: Thyroid-stimulating hormone; Triiodothyronine; Radioimmunoassay; Primary thyroid failure; Effective thyroxine ratio.)
748
A.J.C.P. • December 1977
KUMAR ETAL.
10
350 r =0.73
^
250
8
6 O 150 100
£!•.
>j 4 \ 2
-
\ •• • •
80
•• 60
•ay..
•ill"
SUBNORMAL •••1 • • • • •
SUPRANORMAL
FIG. 1. Distribution of serum T4 levels in 100 primary hypothyroid patients. The solid horizontal line indicates the mean normal level, and the dotted lines indicate ±2 SD.
40
20 TSH Normal 0.2
1:2,500 with or without diffuse goiter, or the diagnosis was confirmed histologically by needle biopsy or surgery. A group of patients (n = 25) who had TG-AB titers less than 1:2,500 or negative titers, but had diffuse firm goiters, were classified as probable Hashimoto's thyroiditis. 3. Post mI therapy hypothyroidism (n = 4). These patients received conventional doses of 131I for treatment of hyperthyroidism due to Graves' disease. 4. Post-thyroidectomy hypothyroidism (n = 7). Radioimmunoassay
of TSH, T4 and T3
Serum TSH, T4 and T3 were measured by doubleantibody radioimmunoassay technic. Methods previously described4-5,7 were used, with slight modifications. Human TSH for labeling and rabbit anti-TSH were obtained from the National Institute of Arthritis, MeTable 1. TSH, T4 and T3 Levels in Primary Hypothyroid Patients at Different Ages
Age (Yr.) 1-20 21-40 41-60 61-80 TOTAL
Total No. (Female + Male)
TSH, MU/ml Mean ± SD
9 (6 + 3) 23 (18 + 5) 42 (32 + 10) 26 (18 + 8) 100 (74 + 26)
147.7 ± 70* 75 ± 54 71 ± 53 62 ± 34 76.7 ± 55
* Significantly higher, P =
