Partial target organ resistance to thyroid hormone.

An 8-year old boy with a small goiter, normal basal metabolic rate (BMR), and elevated serum thyroid hormone levels (thyroxine [T(4)] 19.5 mug per 100 ml, free T(4) 4 ng per 100 ml, triiodothyronine [T(3)] 505 ng per 100 ml) was studied. He had measurable serum thyroid-stimulating hormone (TSH) levels (average 5.5 muU per ml), and the thyroxine-binding proteins, hearing, and epiphyseal structures were normal. There was no parental consanguinity nor were there thyroid abnormalities either in the parents or six siblings.Methimazole, 50 mg daily, depressed thyroxine synthesis (T(4) 10.5, free T(4) 2.5) and caused a rise in TSH to 11 muU per ml. After discontinuation of treatment, TSH declined to 4.2 muU per ml and chemical hyperthyroidism returned (T(4) 21.0 mug per 100 ml, free T(4) 4.2, and total T(3) 475 ng per 100 ml, radioactive iodine [RAI] uptake 68%), but studies of BMR and insensible water loss showed the patient to be clinically euthyroid. Thyrotropin-releasing hormone (TRH), 200 mug i.v., caused a brisk rise in TSH to 28 muU per ml, with T(4) rising to 28 mug per 100 ml, free T(4) to 5.6, and T(3) to 730 ng per 100 ml, thus indicating that the pituitary-thyroid system was intact and that the patient's TSH was biologically active. The unusual sensitivity of the pituitary cells to TRH in spite of the markedly elevated serum thyroid hormone levels also suggested that the pituitary was insensitive to suppression by T(3) or T(4). Serum dilution studies gave immunochemical evidence that this patient's TSH was normal. Neither propranolol, 60 mg, chlorpromazine, 30 mg, nor prednisone, 15 mg daily, influenced thyroid indices. Steroid treatment, however, suppressed the pituitary response to TRH, T(3) in doses increased over a period of 12 days to as much as 150 mug daily caused a rise in serum T(3) to above 800 ng per 100 ml, a decline of T(4) to euthyroid levels (T(4) 9.5 mug per 100 ml, free T(4) 1.6 ng per 100 ml), suppression of the RAI uptake from 68% to 35%, and marked blunting of the responses to TRH, but the BMR and insensible water loss remained normal. The data suggest that the patient's disorder is due to partial resistance to thyroid hormone.

Absence of thyroid-stimulating antibody and long acting thyroid stimulator in relatives of Graves' disease patients.

None of the 76 euthyroid relatives of patients with Graves' disease had detectable LATS in their serum nor was thyroid-stimulating antibody (TSAb), assessed by an increment of cAMP in human thyroid slices, detected in any of the 60 sera tested. Seven of 41 were slightly positive for TSH binding-inhibiting immunoglobulin (TBII). Nineteen of 73 sera were positive (greater than 1:1600) for antibody to thyroid antimicrosomal antigen, of which 4 were also positive (greater than 1:400) for antibody to thyroglobulin; 3 of the 19 had a slightly elevated basal TSH which rose excessively after TRH. Thus, although these euthyroid relatives had evidence of thyroid immunological defects, a thyroid-stimulating antibody was not found.

Transient thyrotoxicosis in an infant delivered to a long-acting thyroid stimulator (LATS)- and LATS protector-negative, thyroid-stimulating antibody-positive woman with Hashimoto's thyroiditis.

A thyrotoxic infant was delivered to a woman with a long-standing history of Hashimoto's thyroiditis, but with no evidence of Graves' disease. Long-acting thyroid stimulator (LATS) and LATS protector were absent, but thyroid-stimulating antibody was transiently present in the infant and markedly and persistently elevated in the mother. It is concluded that the maternal level of thyroid-stimulating immunoglobulins determines the presence and duration of transient neonatal thyrotoxicosis, and that thyroid-stimulating antibody is distinct from LATS and LATS protector.

Hyperthyroidism in Tasmania following iodide supplementation: measurements of thyroid-stimulating autoantibodies and thyrotropin.

Serum thyroid-stimulating autoantibodies (LATS and LATS protector) and thyrotropin (TSH) concentrations were measured in the serum of 30 patients with hyperthyroidism living in Tasmania who developed their disease following correction of iodine deficiency by addition of iodate to the bread. Patients were grouped according to thyroid scan results. None of 8 patients with autonomous thyroid nodules had thyroid-stimulating autoantibodies. These were present in both of the patients with uniform thyroid scans and 14 of 20 patients (70%) with irregular scans without demonstrated localized autonomy. Serum TSH, measured by immunoassay of concentrated serum extracts, was 0.15 muU/ml or less in all patients, below the range of 0.35 to 2.60 muU/ml found in normal subjects. Only 6 (20%) of the 30 patients failed to show either localized autonomy or thyroid-stimulating autoantibodies. In most regards these patients resembled those with antonomous nodules. The findings support the conclusion that the increased incidence of phyerthyroidism in Tasmania was due to an increased supply of iodine to patients with latent hyperthyroidism whose thyroid glands, due to the presence of toxid nodule(s) or thyroid-stimulating autoantibodies, were unresponsive to control by TSH deprivation. There was no evidence for additional pathogenic mechanisms

Dissociation of serum LATS activity and hyperfunction and autonomy of the thyroid gland in Graves' disease.

LATS was measured with the double isotope technique in IgG serum concentrates of 23 patients with Graves' disease before treatment and of 18 patients during treatment with carbimazole and triiodothyronine. LATS activity was present in 18 out of 23 patients before treatment (78%). When the second measurement was taken into account the incidence did increase to 95%. No difference could be found in the mean values of total thyroxine, thyroid 131-I uptake and thyroid weight of the group of LATS positive and LATS negative patients before treatment. Also no relation could be established between LATS activity and suppressibility of thyroid 131-I uptake during treatment. It was found that LATS positive patients who suppress during therapy have lower initial LATS blood levels than LATS positive patients who remain unsuppressed. It is concluded that it is more likely that LATS is a "marker" of Graves' disease rather than the cause of the hyperthyroidism.

Methods for separation of long-acting thyroid stimulator (LATS) from sera containing LATS and TSH.

Methods were devised for separation of long-acting thyroid-stimulator (LATS) from TSH in serum containing both thyroid stimulators by using Rivanol, concanavalin A (con A), or staphylococcal protein A. When 3-5 volumes of 0.5% Rivanol solution were mixed to serum containing TSH or LATS activity, LATS activity remained mainly with IgG in the supernatant fraction. On the contrary, TSH activity was precipitated. When 10 mg con A was added to 1 ml test serum, almost all TSH activity was precipitated, but LATS activity remained in the supernatant fraction, which consisted mainly of IgG and albumin. Almost all LATS activity and part of the TSH activity were precipitated by addition of more than 7.5% polyethylene glycol (PEG), which was therefore not useful for separation of the stimulators in serum. Affinity chromatography on staphylococcal protein A-Sepharose was also found to separate the two thyroid stimulators in serum. By this method LATS-immunoglobulin bound to the protein A column, but no binding of the biologic and immunologic activity of TSH was observed. The protein A method seems the most useful of these four methods for complete separation of both stimulators.

Fetal tachycardia associated with intrauterine fetal thyrotoxicosis.

Tachycardia in both fetuses of a twin gestation was documented in a mother who had undergone subtotal thyroidectomy 8 years prior to her present pregnancy. Maternal and fetal plasma concentrations of long-acting thyroid stimulator (LATS) and amniotic fluid 3,3',5'-triiodothyronine (reverse T3) were determined. All values were consistent with the diagnosis of fetal thyrotoxicosis, as were cord blood studies performed on the fetuses post partum. Significant concentrations of LATS were present in fetal cord blood. The first fetus survived but suffered hyperthyroidism during the first 3 neonatal weeks. The second twin died, possibly of fetal thyrotoxicosis. These studies suggest that in women with a history of thyrotoxicosis, high levels of maternal LATS may in some instances provoke fetal thyrotoxicosis, which can be diagnosed by the measurement of amniotic fluid reverse T3.

[Long term effects of the treatment of the Graves' disease by 4 different therapeutics (author's transl)]. / Effets à long terme du traitement de la maladie de Basedow. Comparaison de 4 plans thérapeutiques.

166 patients suffering of Graves' disease have been treated between 1967 and 1971 with 4 different methods (Carbimazole alone, Carbimazole + Surgery, 131 I, 131 I + Carbimazole between 10th and 50th days). The choice was conducted by the volume of the gland and the age of the patient. Isotope was calculated to deliver 7 000 rads in 76 cases and 10 000 rads in 17 more severe cases (cardiothyreosis). 129 patients were submitted to a long term follow up. Medical treatment gave euthyroidism in 34/47 after a mean duration of 8 months. 1/3 to 1/2 of the patients relapsed between 1 to 9 years. Surgical treatment was successful in 25/26 after a total period of 5,5 months. 8 relapsed and 3 became hypothyroid. Relapses were more frequent after bilateral subtotal thyroidectomy than after total lobectomy + subtotal contralateral lobectomy. Isotope gave a complete cure in 14 patients (delay 4,1 months) and in 34, a complementary treatment was necessary (delay 13,5 months). Relapses (12/94) were detected in general after 2 years. The results were the same after 7 000 ans 10 000 rads doses and in the patient receiving, or not, systematically carbimazole. The treatment of Graves' disease is long and difficult. An excellent result is obtained only in half of the cases. 1/3 of these good results needs less than 6 months and 2/3 12 months. A thyroid of less than 40 g include after surgical treatment or after isotopic irradiation an increasing risk of hypothyroidism.

Testing thyroid function.

From the foregoing discussion, it is clear that no single test provides sufficient information to justify its use alone as a single screening test. In vitro tests have now replaced in vivo procedures in the vast majority of patients. Because of the frequency of abnormalities in TBP concentration, the estimation of total T4 should be accompanied by a T3 resin uptake to provide the free thyroxine index or alternatively, a normalized T4 test (Quantisorb or ETR) is preferable. In patients with suspected hyperthyroidism, the initial laboratory evaluation should be an estimate of free T4 and a total serum T3 determination. Whereas the majority of hyperthyroid patients exhibit elevated free T4 levels, a smaller but variable percentage will exhibit only an elevated T3 level. The diagnosis mients where equivocal tests do not provide a diagnosis. In patients with suspected hypothyroidism, estimations of T4 and T3 provide evidence of diminished thyroidal secretion. The diagnosis should be confirmed by demonstration of an elevated TSH level. Normal or low TSH levels point to a diagnosis of pituitary hypothyroidism which can be confirmed by TRH stimulation. The finding of low normal or subnormal T4, normal T3 and elevated TSH levels suggest "compensated hypothyroidism". Estimation of thyroid autoantibodies may confirm the diagnosis of autoimmune thyroiditis. It is emphasized that the approach to testing thyroid function should be an adequate clinical assessment so that selection of the appropriate test(s) currently available leads to a diagnosis of great certainty in most cases.