Reciprocal relation of thyroid-stimulating hormone and thyroid-stimulating immunoglobulin in a patient with endogenous subclinical hyperthyroidism.

A 72-year-old white woman with an abnormal serum thyroid-stimulating hormone (TSH) concentration was referred to our facility for a comprehensive evaluation. Circulating thyroxine (T4) and free thyroxine (FT4) concentrations were all in the normal range. Tri-iodothyronine (T3) concentrations were in the low end or slightly below the normal range. TSH was detectable but was below the limits of the normal range. The patient was clinically euthyroid and was receiving medication only for treatment of hypertension. The clinical and laboratory thyroid function status was consistent with a diagnosis of subclinical hyperthyroidism. The physical examination did not reveal thyroid enlargement, nor was there any evidence for the presence of thyroid nodules or ocular changes suggestive of Graves disease. Among thyroid autoantibodies of particular interest was the presence of a moderate thyroid-stimulating immunoglobulin (TSI) level that was stable and consistently present during a 7-month observational period. At 13 months after the initial visit, TSI antibodies were absent and TSH concentration had returned to the normal range. Based on the TSH agonist activity of TSI and the observed reciprocal relation of TSI and TSH, there was no need to suggest pituitary hypersensitivity to thyroid hormone.

Low T3 syndrome in psychiatric depression.

In euthyroid sick syndrome [non-thyroidal illness (NTI)], a number of investigators have described TSH and serum thyroid hormone abnormalities, low T3, low T3 and T4, increased T4, low TSH, etc. Those cases of NTI where there is only T3 decrease [and normal serum T4, free T4 (FT4), and TSH levels] are specifically referred to as low T3 syndrome. However, the information in regard to low T3 syndrome in psychiatric subjects who are clinically euthyroid and do not have any other systemic illness is scanty. In our facility, since thyroid function is routinely assessed in psychiatric patients at admission, this provided the opportunity to study low T3 syndrome in a large group of psychiatric patients. Out of 250 subjects with major psychiatric depression, 6.4% exhibited low T3 syndrome (mean serum T3 concentration 0.94 nmol/l vs normal mean serum concentration of 1.77 nmol/l). The low T3 levels could not be ascribed to malnutrition or any other illness and the metabolic parameters were all normal. Possible mechanisms contributing to low T3 are discussed. The depression might constitute an illness having the same relation to low T3 as found in the low T3 syndrome previously described in euthyroid sick subjects. The present findings, besides describing low T3 syndrome in psychiatric patients without systemic illnesses, suggest the possibility of subgrouping in clinical psychiatric depression which may have a broader clinical significance.

Apparent increase in type I 5'-deiodinase activity induced by antiepileptic medication in mentally retarded subjects.

BACKGROUND/OBJECTIVES: Thyroid function measurements in 3 mentally retarded patients treated with antiepileptic drugs (phenytoin or carbamazepine) showed normal thyroid-stimulating hormone (TSH) responses in spite of markedly low levels of total thyroxine (T(4)), triiodothyronine (T(3)), and free thyroxine (FT(4)) concentrations; free triiodothyronine (FT(3)), as well as mean thyroxine-binding globulin (TBG) concentrations were normal. The objective of the present investigations was to determine if antiepileptic medication in these patients contributed to the disparate TSH and thyroid hormone (TH) levels. METHODS: Thyroid tests and other laboratory parameters were measured by conventional techniques. RESULTS: Circulating TH changes noted in retarded patients were similar to those observed in control subjects receiving carbamazepine alone. Reverse T(3) (rT(3)) levels in all patients were either undetectable or below the normal range. CONCLUSIONS: As type I 5'-deiodinase has a higher affinity for rT(3) than T(4), an increased activity of this enzyme would enhance rT(3) deiodination and reduce serum rT(3) concentration whereas enhanced T(4) deiodination would aid in normalizing intracellular FT(3) concentration. The finding of normal serum FT(3) concentration was consistent with normal TSH response and clinical euthyroidism in both retarded and control subjects. While phenytoin-induced increase in type I 5'-deiodinase has been previously noted, the present studies demonstrate a similar effect of carbamazepine on 5'-deiodinase.

Inhibition of serum protein binding of thyroxine in a hypothyroid patient with familial dysalbuminemic hyperthyroxinemia.

OBJECTIVE: To investigate unusual free thyroxine (FT4) responses to T4 replacement doses in a hypothyroid patient with familial dysalbuminemic hyperthyroxinemia (FDH). METHODS: In this FDH hypothyroid patient, serum FT4 concentration by equilibrium dialysis and T4, triiodothyronine (T3), and thyroid stimulating hormone (TSH) determinations were supplemented by thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) measurements. RESULTS: Initial thyroid function tests were compatible with hypothyroidism and FDH (T4 = 78 nmol/L, T3 = 1.08 nmol/L, FT4 = 11.6 pmol/L, TSH = 45 mU/L). When she was initially treated with T4 (0.112-0.088 mg/day) there was an increase in FT4 concentration to hyperthyroid levels accompanied by TSH inhibition (FT4 = 31-51 pmol/L, TSH = <0.03 mU/L); the patient also complained of intolerance and nervousness, and T4 treatment was discontinued. Concentrations of thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) were normal. When T4 therapy was later resumed at a dosage of 0.075 mg/day, there was a marked increase in percent dialyzable T4. The elevation in percent dialyzable T4 during T4 replacement in a patient with FDH is unusual in view of the very large T4 binding capacity of FDH albumin. The presence of an inhibitor that reduced T4 binding by both TBG and FDH albumin probably explains the elevation in percent dialyzable T4 during T4 treatment. CONCLUSIONS: This FDH patient represents the first case of a putative inhibitor of T4 binding to both TBG and FDH albumin. The inhibition of T4 binding by these disparate proteins suggests that the inhibitor effect is mediated nonspecifically.

Cerebral vascular amyloid deposition in rabbits with induced thyroglobulin immunity.

Cerebral amyloid angiopathy (CAA) occurs in humans along with the neuritic amyloid plaques in Alzheimer's disease, in several familial (inherited) syndromes, and in a sporadic form that increases in prevalence with age to attain a rate of about 60% after age 90. In the non-Alzheimer conditions, it is often accompanied by cerebral hemorrhage and sometimes also by dementia. We report here the experimental induction of cerebrovascular amyloid (CVA) in thyroglobulin (Tg)-immunized rabbits. The vascular deposits in these rabbits are comparable to that seen in humans in that they primarily involve arterioles, venules, and capillaries and exhibit microscopic and ultrastructural characteristics similar to the human lesion. Prominent congophilic vascular lesions in the brain were seen in three out of six Tg-immunized rabbits, whereas less striking basement membrane thickening was evident in three other experimental animals, probably reflecting individual variations in vascular responses to actively induced Tg immunity. Occasional primitive amyloid plaques were also encountered adjacent to vascular lesions. These observations are of particular interest since in other experimental models, cerebral vascular amyloid deposits have not been observed, thus suggesting that immunopathogenic events induced by active Tg immunization may be unique in their effects on the cerebral vasculature.

Persistence of low serum thyroid hormone levels in a Graves' disease patient receiving supraphysiologic L-thyroxine replacement therapy.

A patient with Graves' disease was treated with radioactive iodine. For several years following treatment, the patient displayed clinical hypothyroidism and persistently low serum thyroxine (T4) and triiodothyronine (T3) levels despite large T4 replacement dosage (0.3-0.4 mg L-thyroxine daily). A defect in T4 absorption was considered unlikely since absorption of fat soluble materials (vitamins A and E) was essentially normal as reflected by their serum concentrations. Abnormalities in serum protein binding of T4 especially by immunoglobulins were suspected; however, thyroid hormone binding antibodies were absent. Thyroxine binding prealbumin (TBPA) levels were either frankly elevated or in the upper normal range and such variations were mirrored by retinol binding protein (RBP) concentrations. Thyroxine binding globulin (TBG) concentration was normal. A surprising finding was an elevated percent dialyzable thyroxine (.041%; normal range, .018-.034%) in spite of a normal concentration of TBG. Serum free fatty acid levels were also elevated. The marked increase in percent free T4 (FT4) fraction together with a low serum total T4 concentration resulted in normal or marginally elevated FT4 levels. An increase in T4 metabolic clearance as suggested by the elevated percent FT4 fraction was corroborated by steady state serum T4 values observed following changes in T4 dosage.(ABSTRACT TRUNCATED AT 250 WORDS)

Coexistence of familial dysalbuminemic hyperthyroxinemia with familial hypercholesterolemia and multiple lipoprotein type hyperlipidemia.

Familial dysalbuminemic hyperthyroxinemia (FDH), an autosomal disorder characterized by an increase in serum albumin binding of thyroxine, has been encountered in a family who was also found to have both familial hypercholesterolemia (FHC) and multiple lipoprotein type hyperlipidemia (MLH). One subject with FHC and two subjects with MLH had FDH. Although some of the laboratory parameters in hyperlipidemic patients with FDH were suggestive of hyperthyroidism, the dialyzable free thyroxine concentrations were in the normal range and the patients were clinically euthyroid. The significance of the occurrence of FDH in hyperlipidemic subjects with hypothyroidism has been discussed, especially in regard to the longer time interval that may be needed to achieve an amelioration of the hypothyroid state during treatment with a normal maintenance dose of thyroxine. Treatment of FDH patients with other drugs may require an altered dosage if the drug binds to the atypical albumin fragments characterizing this disorder.

Modulation of thyroid parameters by exogenous thyroxine in familial dysalbuminemic hyperthyroxinemia.

A patient with familial dysalbuminemic hyperthyroxinemia (FDH) was given graded doses of exogenous thyroxine (0.2 mg/d for 2 weeks; 0.4 mg/d for 2 weeks; 0.6 mg/d for 2 weeks) to study modulation of various thyroid parameters. The plasma concentration of the serum transport proteins, thyroxine binding globulin (TBG), sex hormone binding globulin (SHBG), and cortisol binding globulin (CBG) as well as serum thyroxine (T4), triiodothyronine (T3), absolute free thyroxine (FT4), and serum protein binding of T4 tracer were measured. At the end of T4 treatment, T4 and T3 were increased by 151% and 78%, respectively. The FT4 increased (157%), while the percent dialyzable free T4 fraction (DFT4) showed no significant change. SHBG, a protein sensitive to thyroid hormone (TH) action, increased 148% (from 0.23 to 0.57 micrograms/dL) after treatment but this concentration was still in the normal range; TBG and CBG decreased by about 16%. Analysis of the electrophoretic 125I-T4 distribution pattern in serum during T4 treatment showed essentially no change in TBG-bound T4 (percent tracer carriage X total T4), while there was a progressive increase in albumin-bound T4 (341% increase over pretreatment value) and a lesser increase in prealbumin (TBPA)-bound T4 (187%). These observations describing alterations in TH action, serum T4-protein binding, and the failure of percent DFT4 to increase with elevation in serum total T4 are of clinical significance in evaluating thyroid function parameters in FDH patients undergoing TH treatment.

Potentiation of thyroxine 5-deiodination by aminotriazole.

Aminotriazole, a goitrogen, in addition to its known inhibitory effects on the thyroid, demonstrated a unique effect on peripheral deiodination of thyroxine (T4). In contrast to the well-known peripheral effects of goitrogens such as propylthiouracil in inhibiting 5'-deiodinase activity, i.e., to effect a decrease in T4 to triiodothyronine (T3) conversion, aminotriazole had no effect on the 5'-deiodinative pathway. Rather, this goitrogen appeared to stimulate the alternative pathway, viz. T4 5-deiodination, resulting in an increased reverse triiodothyronine (rT3) serum concentration. This was shown in comparisons of serum T4, T3 and rT3 concentrations and serum T3/T4 and rT3/T4 ratios between rats treated with aminotriazole and T4, and rats treated with T4 alone. The finding that aminotriazole may specifically enhance T4 5-deiodination, independently of T4 5'-deiodination, is novel, as this has not been observed in the case of other goitrogens. It is of interest that this goitrogen is devoid of sulphur, which is a prominent constituent of thiourylene compounds which have been noted to affect 5'-deiodination. The potentiating effect of aminotriazole on 5-deiodination of T4 was not attributable to dietary factors.