Comparison of standardized initial doses of two antithyroid drugs in the treatment of Graves' disease

Objectives. To obtain a simple standard regimen, suitable for general practice, and based upon the addition of antithyroid drug plus thyroxine for attaining euthyroidism in patients with Graves' disease. Design. Prospective, randomized trial of patients with Graves' disease followed for 3 months after the initiation of therapy with an antithyroid drug and combined with the later addition of triiodothyronine to keep the patient euthyroid. The patients were randomized, according to birth date, between methimazole and propylthiouracil. Three dose schemes were tested for each antithyroid drug. Setting. The study was performed at the thyroid outpatient units of two general hospitals, with the patients having been referred from primary care. Subjects. Ninety-four patients with Graves' disease who were suitable for treatment with antithyroid drugs. Interventions. The patients were allocated into six groups. Three groups received methimazole (10 mg every 6th, 8th or 12th h) and three received propylthiouracil (100 mg every 6th, 8th or 12th h). Twenty micrograms of triiodothyronine was added when the patients were euthyroid to avoid hypothyroidism. Main outcome measures. The lowest serum free thyroxine level within 3 months of the initiation of the antithyroid treatment. Results. Fourteen per cent of the patients on methimazole 10 mg every 12th h and 29% on propylthiouracil 100 mg every 12th h did not achieve euthyroidism within the 3-month observation period. All but one patient on methimazole 10 mg every 8th h or propylthiouracil 100 mg every 8th h reduced the free serum thyroxine levels to the normal or hypothyroid range within the observation period. All of the patients on methimazole 10 mg every 6th h and 56% on propylthiouracil 100 mg every 6th h reduced the serum T4 values into the hypothyroid range within the period. Conclusion. A standard regimen, based upon the addition of methimazole 10 mg every 8th or 6th h or propylthiouracil 100 mg every 8th or 6th h and followed by the addition of thyroxine or triiodothyronine when euthyroid to avoid hypothyroidism, seems to be suitable for attaining euthyroidism within 3 months in patients with Graves' disease. A dose scheme based on methimazole 10 mg every 12th h or propylthiouracil 100 mg every 12th h were found to be unsuitable due to an unacceptably high incidence of failure to attain euthyroidism or hypothyroidism within 3 months.     

Bone metabolism during anti-thyroid drug treatment of endogenous subclinical hyperthyroidism

OBJECTIVE There is recent evidence that both exogenous and endogenous subclinical thyrotoxicoses are associated with decreased bone mineral density. Scanty information is available on bone metabolism in these conditions when euthyroidism is restored. We evaluated the effect of anti-thyroid drug treatment on bone metabolism in endogenous subclinical hyperthyroidism. DESIGN Prospective follow-up study over 2 years during treatment with methimazole, with an untreated control group. SUBJECTS Sixteen post-menopausal women with endogenous subclinical hyperthyroidism associated with multinodular goitre, eight of whom were treated with methimazole. MEASUREMENTS Serum concentrations of free T4, total T3, TSH, osteocalcin, urinary excretion of hydroxyproline and forearm bone mineral density were measured at regular intervals. RESULTS Significant changes in serum osteocalcin concentration or urinary hydroxyproline excretion were not observed in either group. Distal, but not proximal, forearm bone mineral density, expressed as a percentage of the base-line value, was significantly (P < 0.05) higher in the treated than in the untreated subjects in the second year of treatment. CONCLUSION Treatment with methimazole In post-menopausal women with endogenous subclinical hyperthyroidism associated with multinodular goitre can prevent excessive loss of bone, at least in the distal forearm.     

The effect of methimazole pretreatment on the efficacy of radioactive iodine therapy in Graves' hyperthyroidism: one-year follow-up of a prospective, randomized study

The effect of antithyroid drugs on the efficacy of radioiodine (131I) treatment is still controversial. This study evaluated the effect of methimazole pretreatment on the efficacy of 131I therapy in Graves' hyperthyroidism. Sixty-one untreated patients were randomly assigned to receive 131I alone (32 patients) or 131I plus pretreatment with methimazole (30 mg/d; 29 patients). 131I was administered 4 d after drug discontinuation. The calculated 131I dose was 200 microCi/g thyroid tissue as estimated by ultrasound, corrected by 24-h radioiodine uptake. Serum TSH, T4, and free T4 were measured 4 d before 131I therapy, on the day of treatment, and then monthly for 1 yr. Considering cure as euthyroidism or hypothyroidism, based on free T4 measurement, approximately 80% of patients from both groups were cured 3 months after beginning 131I treatment. After 1 yr the groups were similar in terms of persistent hyperthyroidism (15.6% vs. 13.8%), euthyroidism (28.1% vs. 31.0%), or hypothyroidism (56.3% vs. 55.2%). Relapsed patients presented larger thyroid volume (P = 0.002), higher 24-h radioiodine uptake (P = 0.022), and T3 levels (P = 0.002). Multiple logistic regression analysis identified T3 values as an independent predictor of therapy failure. In conclusion, pretreatment with methimazole had no effect on either the time required for cure or the 1-yr success rate of 131I therapy.     

THE SIGNIFICANCE OF THE INITIAL FT4-INDEX FOR THE MANAGEMENT OF SINGLE DAILY DOSE METHIMAZOLE TREATMENT OF HYPERTHYROIDISM

Since the effectiveness of 30 mg methimazole in a single daily dose in gaining initial control of hyperthyroidism may depend largely on patient characteristics, 52 patients (34 with diffuse and 18 with nodular goitre) were investigated in an attempt to determine the relative importance of a number of pretreatment variables. Return to normal thyroid hormone levels after 2 to 6 weeks of treatment appeared to be the rule, although eight of these patients formed notable exceptions (6-20 weeks). The individual duration of treatment until achievement of biochemical euthyroidism correlated with the initial free thyroxine index (r = 0.75, P less than 0.001) and the free triiodothyronine index (r = 0.70, P less than 0.001). For patients with a diffuse goitre it was also related to the thyroid volume estimated by ultrasound (r = 0.73, P less than 0.001). According to multiple linear regression analysis however these variables were found to have no independent prognostic value. The decrease in thyroid volume during initial therapy, the nature of the goitre, a medication compliance score and various other patient variables did not correlate with the effect of treatment. In 12 cases perchlorate discharge tests were performed. The results suggest continued hormone synthesis in patients with highly active iodine trapping as an important mechanism of the postponed attainment of euthyroidism.     

A long-term follow-up study of patients with non-toxic diffuse goitre in Japan

OBJECTIVE Although non-toxic diffuse goitre is a common disorder, little is known of the clinical course of patients. We therefore decided to investigate the long-term clinical outcome of patients with non-toxic diffuse goitre. DESIGN A retrospective study. PATIENTS Of 850 patients with non-toxic diffuse goitre who met our criteria and were seen in our thyroid clinic between 1977 and 1985, 108 who had been followed for from 5 to 14 years (mean 8 years) were entered in this study. All patients fulfilled our criteria having soft diffuse goitres, normal serum TSH and T4 concentrations, and undetectable antithyroglobulin and antithyroid microsomal antibodies. MEASUREMENTS A family history of thyroid disease was obtained and the occurrence of Graves' ophthalmopathy was noted. Serum TSH and T4 concentrations, and antithyroglobulin and antithyroid microsomal antibodies were measured during the follow-up period. Thyroidal radioactive iodine uptake (RAIU), serum free T4 and free T3 concentrations, and TSH binding inhibitory immunoglobulin (TBII) activities were determined in all patients who were subsequently found to have abnormal serum TSH or T4 concentrations or signs of Graves' ophthalmopathy. RESULTS Thirty-six of the 108 patients (33%) had a family history of autoimmune thyroid disease. Elevated serum T4 or free T4 concentrations and depressed serum TSH concentrations were found in six patients during the follow-up period. Hyperthyroid Graves' disease was diagnosed in four of the six patients, subacute thyroiditis in one, and transient post-partum thyrotoxicosis in one. Hypothyroidism was found in one patient who was diagnosed as having transient post-partum hypothyroidism. Euthyroid Graves' disease was diagnosed in one patient. Furthermore, six of these eight patients had a family history of autoimmune thyroid disease in first-degree relatives. CONCLUSION During a prolonged follow-up period of patients with non-toxic diffuse goitre, Graves' disease was found in five of 108 patients (four hyperthyroid Graves' and one euthyroid Graves'), post-partum thyroid dysfunction in two, and subacute thyroiditis in one. Six of these eight patients had a family history of autoimmune thyroid disease in first-degree relatives. Long-term follow-up is necessary for patients with non-toxic diffuse goitre, especially those who have a family history of autoimmune thyroid disease.     

Iodide induces transforming growth factor beta 1 (TGF-beta 1) mRNA in sheep thyroid cells.

We examined TGF-beta mRNA levels in primary sheep thyroid cell cultures to determine whether the inhibitory effects of iodide on thyroid cells could be explained by an induction of TGF-beta mRNA and if this induction was mediated by iodine organification. Thyroid cells were incubated with TSH and five additives (insulin, somatostatin, growth hormone, transferrin, and glycyl-L-histidyl-L-lysin) for 2-3 weeks and then were exposed to sodium iodide (NaI) or 1-methylimidazole-2-thiol (methimazole, MMI), or both for 72 h. Iodide at 10(-6) M and 10(-4) M significantly increased the amount of TGF-beta mRNA as determined by Northern blot analysis with a rat TGF-beta 1 cDNA probe. This increase in TGF-beta 1 mRNA was abolished by the addition of methimazole, an inhibitor of organification. These data indicate that the effects of iodide on thyroid growth and function may be mediated by a process that involves organification of iodide and increases in TGF-beta 1 mRNA levels.     

Inhibition of cyclic AMP formation by iodide in suspension cultures of porcine thyroid follicle cells

In the present study porcine thyroid cells in suspension cultures were employed to investigate the suppressive effect of iodide on adenylate cyclase under basal conditions and following incubation with TSH, PGE1, cholera toxin and forskolin. Within 30 min of incubation with iodide (half-maximal effect 10(-5) M), inhibition was established and remained unchanged up to 40 h of culture. The inhibitory action was abolished by methimazole. TSH, PGE1, cholera toxin and forskolin stimulated cAMP accumulation 10-, 3-, 24- and 22-fold, respectively. Iodide pretreatment reduced basal cAMP levels and also made the cells less sensitive to stimulation by the various agents. High concentrations of TSH or PGE1 could not overcome the suppressive influence of iodide, whereas with high concentrations of cholera toxin and forskolin the reduction in cAMP levels in iodide-treated cultures was less pronounced. Membranes isolated from iodide-treated cultures produced significantly lower amounts of cAMP compared to control membranes. Furthermore, iodide did not inhibit basal or forskolin-stimulated cAMP production in human fibroblasts. The results demonstrate that iodide via an iodination-dependent mechanism influences cAMP generation in thyroid cells. It is suggested that the inhibitory activity, which has a long half-life, involves stable modification of the membrane-localized catalytic unit of adenylate cyclase such that its activation by the regulatory unit is rendered less efficient.     

The effect of treatment with levothyroxine or iodine on thyroid size and thyroid growth stimulating immunoglobulins in endemic goitre patients

OBJECTIVE We assessed the effect of levothyroxine or iodine on thyroid size and on thyroid growth stimulating immunoglobulins in endemic goitre patients. DESIGN Levothyroxine or iodine was given orally in an open randomized prospective study (100 and 200 μ g respectively). PATIENTS Thirty-seven euthyroid patients with diffuse iodine deficiency goitres and thyroid growth stimulating immunoglobulins were studied. MEASUREMENTS Thyroid size, thyroid growth stimulating immunoglobulins (mitosis arrest assay), basal TSH, free T3, free T4, thyroid anti-microsomal antibodies, anti-thyroglobulin antibodies, anti-TSH receptor antibodies and urinary iodine excretion were measured. RESULTS Thyroid size decreased significantly in both groups, in the levothyroxine group more than in the iodine treated group. Thyroid growth stimulating immunoglobulins levels also decreased significantly in both groups. Between groups there was no statistically significant difference. A statistically significant correlation between thyroid growth stimulating immunoglobulins reduction profiles and goitre size reduction could not be established. TSH levels became suppressed in the levothyroxine group while the T4 values rose; in the iodine treated group TSH levels stayed constant as did T4. None of the patients developed thyroid microsomal or thyroglobulin auto-antibodies and/or hyperthyroidism during the treatment. CONCLUSIONS Levothyroxine as well as iodine was effective in reducing thyroid size as well as thyroid growth stimulating immunoglobulins levels in endemic goitre patients. Since in both groups TSH levels were not related to thyroid size reduction, other factors than TSH suppression must be responsible for the observed thyroid size reduction. Iodine itself by virtue of its antiproliferative action on thyrocytes may have had a direct action on the goitre reduction during iodine treatment; however, the levothyroxine dose, containing less iodine, had a similar effect. A complicated picture hence emerges with regard to factors involved in the shrinkage of iodine deficiency goitre during thyroxine or iodine therapy. These findings indicate that TSH and thyroid growth promoting immunoglobulins are not the only influences on the size of endemic goitres, although it cannot be excluded that these two factors contribute to influence the pathogenetic process.     

Altered responsiveness to thyrotropin in thyroid slices of Graves' disease preoperatively treated with excess iodide.

In a previous paper, we demonstrated that the acute administration of excess iodide inhibits the adenylate cyclase-cAMP system in mouse thyroid lobes. In the present study, we examined whether presurgical therapy with stable iodide reduces the responsiveness to TSH in thyroid tissues from patients with Graves' disease. Eight patients with Graves' disease were presurgically treated with methimazole and stable iodide and six were given methimazole alone. Normal tissues from five patients with thyroid nodules were also tested. We have found that stimulation by TSH (5 and 50 mU/ml) of cAMP formation in thyroid slices from patients preoperatively treated with methimazole and iodide is significantly less than in slices from patients treated with methimazole alone. Similar observations were also made with other thyroid stimulators, such as prostaglandin E2 and 4-methylhistamine. Furthermore, thyroid slices from patients treated with methimazole alone responded to TSH to the same degree as slices of normal tissues. The data suggest that one of the reasons for the hyporesponsiveness to TSH in thyroids from patients with Graves' disease is preoperative treatment with stable iodide.     

TSH BINDING-INHIBITING ANTIBODIES IN HYPERTHYROIDISM: RELATIONSHIP TO CLINICAL SIGNS AND HORMONE LEVELS

TSH binding-inhibiting antibody (TBIAb) activity was measured in 809 European patients with different forms of hyperthyroidism. Distribution of these TBIAb was skewed, with a peak in the range of normal controls, and an ill defined, not clearly separated peak at higher levels of TSH displacement. There was no unequivocal separation of two possible subgroups of hyperthyroidism (immunogenic and non-immunogenic). TBIAb distributions of patients with and without endocrine ophthalmopathy (EO) overlapped considerably. Although patients with Graves' disease, arbitrarily defined by the presence of endocrine ophthalmopathy or diffuse nuclide uptake by thyroid scanning, had mostly elevated TBIAb activity, 24.3% had values within the range of normal controls (mean + 2SD). Patients with diffuse thyroid uptake had significantly higher TBIAb levels than patients with nodular scan findings. In Graves' disease, TBIAb activity was positively correlated with the severity of endocrine ophthalmopathy, the size of the thyroid, and the serum levels of total and free triiodothyronine. There was no influence of age, sex, pretreatment, or regional iodine supply. These results suggest (1) that the clinical manifestations of Graves' disease are statistically related to TBIAb activity and (2) that separation of immunogenic and non-immunogenic forms of hyperthyroidism by means of TBIAb determination is unsatisfactory. The almost continuous distribution of TBIAb points to insufficient sensitivity of the present technique and raises doubts as to whether TBIAb values can be reliably classified as 'positive' or 'negative'.     

Administration of a single dose of recombinant human thyrotrophin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres

OBJECTIVE: Patients with very large multinodular goitres, frequently found among elderly people, often suffering from cardiovascular or other disabling disorders, may be considered as unsuitable for surgery. We have evaluated the feasibility of relatively high-dose 131I therapy in such patients. As subclinical or clinical hyperthyroidism is commonly found in these patients, associated with a low radioiodine (RAI) uptake at 24 h, we pretreated a group of patients with a single intramuscular injection of recombinant human TSH (rhTSH 0.45 mg) in order to increase the uptake of the therapeutic dose of RAI. DESIGN AND PATIENTS: Forty-one patients with large, long-standing multinodular goitres, were recruited for this study. After a careful and detailed clinical and laboratory evaluation, 34 patients (28 women, six men) were included and randomly assigned to group 1 (control, n = 17, 15 women, two men, age 63.1 +/- 11.2 years) receiving only RAI. Patients in group 2 (n = 17, 13 women, four men, age 63.6 +/- 12.3 years) received the therapeutic dose of RAI, having been pretreated (24 h) with 0.45 mg of rhTSH. Both groups of patients were submitted to a low iodine diet, 4-6 months before RAI treatment, while seven thyrotoxic patients also received methimazole (40 mg/day) until they reached euthyroidism. Ultrasonographic studies were performed for all patients and fine-needle aspiration biopsy (FNAB) were performed on one or two nodules before RAI treatment. RAI was given as a single oral dose to the hospitalized isolated patients. Blood samples for thyroid function tests and serum thyroglobulin (Tg) were collected daily during the first week following RAI treatment, and at 1, 3, 6, 9 and 12 months thereafter. MEASUREMENTS: Goitre volume was estimated by computed tomography scan. Thyroid function tests (total T3, free T4, TSH and serum Tg) were assayed with commercial kits. Urinary excretion of iodine was assayed by the Sandell-Kolthoff method. RESULTS: After the RAI therapeutic dose, serum thyroid function tests were carried out daily for the first week and then on a monthly basis (1, 3, 6, 9 and 12 months). Serum TSH levels rose to a peak level of 45.9 +/- 19.1 mU/l (24 h) in group 2 returning to normal at 72 h. Free T4 serum concentrations rose significantly to 59.35 +/- 21.61 pmol/l at 48 h (in group 2) returning to normal at 7 days. Similarly, serum TT3 also peaked above normal levels only in group 2 (6.12 +/- 1.89 nmol/l) at 24 h. Serum Tg increased in both groups (significantly higher in group 2) and remained elevated during the following 12 months. Both groups had a significant reduction in goitre volume at 12 months (group 2: 57.8%vs. group 1: 39.7%, P < 0.05). Hypothyroidism was detected after RAI treatment, respectively, in 21.4% (group 1) and 64.7% (group 2), of the patients at 12 months. CONCLUSIONS: Our results indicate that the use of hTSH increased the efficacy of the RAI therapeutic dose. This was basically due to an increased uptake of the radionuclide (as a consequence of the higher serum TSH levels) and a more extensive distribution of 131I within the nodules of the multinodular goitre. A more intense radiation effect was reflected in there being a higher output of serum Tg and thyroid hormones (group 2). As a consequence this group had a significantly higher reduction of the goitre volume. Also incidence of hypothyroidism post-RAI was significantly higher in group 2. We concluded that pretreatment with rhTSH in elderly patients with large multinodular goitres increases the uptake of the RAI therapeutic dose, thereby significantly reducing the multinodular goitre volume and relieving the compressive symptoms with relatively few side-effects.     

Inhibition by iodide of the activation of the thyroid cyclic 3',5'-AMP system.

The action of iodide on the cyclic AMP system of dog thyroid slices has been studied. Iodide inhibits the enhancement of cyclic AMP accumulation in the presence of TSH. Such an effect is also observed in horse, beef and sheep thyroid slices, but not in dog kidney slices stimulated by parathyroid hormone or in rat parotid slices stimulated by isoproterenol. The effect in dog thyroid slices is suppressed by 1mM NaClO4, 1mM methimazole and 1mM propylthiouracil. Similar data have been obtained for prostaglandin E1 stimulation. Effects of thyrotropin mediated by cyclic AMP, i.e., activation of iodothyronine secretion, 1-14C-glucose oxidation, and lactate formation, were also inhibited by iodide but not by iodide and methimazole. Similar activations when caused by dbcAMP were not inhibited by iodide. The data suggest a model in which an intracellular agent resulting from the oxidation of iodide acts on the thyroid cyclic AMP system.     

Cell necrosis and apoptosis are differentially regulated during goitre development and iodine-induced involution

Necrosis and apoptosis coexist in the thyroid during goitre development and involution, but little is known about their respective causes. To test the possible role of free radicals, we analysed separately necrosis and apoptosis in male Wistar rats with depressed or normal antioxidant protection. Vitamin E-deficient and -sufficient rats were made goitrous with perchlorate in drinking water; involution was induced by repeated injection of NaI, without or with methimazole. Increase of thyroid malondialdehyde concentration and decrease of glutathione peroxidase activity confirmed the depressed antioxidant protection in vitamin E-deficient rats. Plasma thyroxine and TSH levels were not modified. Necrosis (swollen cells) and apoptosis (pyknotic cells) were quantified on histological sections. In vitamin E-sufficient rats, dead cells were very rare in control thyroids, increased 3-fold in goitre and still further during involution. Necrotic epithelial cells predominated in the goitre and their number declined after iodide supplementation, without or with methimazole. In contrast, the number of apoptotic cells and the caspase-3 activity were increased in goitre and further increased after involution, with two-thirds of pyknotic cells being observed in the interstitium. Apoptosis was prevented by methimazole. Vitamin E deficiency significantly increased total cell death and epithelial cell necrosis and induced the occurrence of much cell debris in the follicular lumen during involution, with no modification of the apoptotic reaction. These results show that the type of cell death is differentially regulated during goitre development and involution: necrosis is related to the oxidative status of the cells, while apoptosis comes with iodine-induced involution.     

HYPOTHYROIDISM AND GRAVES' DISEASE AFTER MANTLE IRRADIATION: A FOLLOW UP STUDY

Abstract Fifty of 66 patients whose thyroid function had previously been assessed 7–139 months after irradiation for Hodgkin's disease were re-evaluated 35 ± 3 months later. They could be divided into three groups: those whose thyroid function had been normal in the first study (N= 26), those who had had asymptomatic impaired thyroid reserve (N= 19), and those in whom evidence of Graves' disease had developed (N= 5). The 26 patients who had been euthyroid when first studied had developed significant increases in mean throid-stimulating hormone (TSH) levels basal and following thyrotrophin releasing hormone) without changes in mean free thyroxine index (FTI). In three of these patients, each studied within six years of irradiation, basal TSH had risen to hypothyroid levels. There were no significant changes in mean FTI or basal and peak TSH in 19 patients who had demonstrated impaired thyroid reserve in the first study. The cumulative incidence of impaired thyroid reserve in the total cohort is now 30/66 (45%) but only one of these 30 has developed clinical hypothyroidism. Five patients developed evidence of Graves' disease. Two patients with thyrotoxicosis and one with euthyroid Graves' disease were found in the initial study. On re-evaluation, a third patient had developed frank thyrotoxicosis and another euthyroid Graves' disease, giving a cumulative incidence of Graves' disease of 5/66 (7%). Three of these five were HLA-DR3 and three had measurable thyrotrophin binding inhibiting immunoglobulins. We conclude that impaired thyroid reserve continues to develop within six years of mantle irradiation in adults but once established appears to remain stable. There also appears to be a high incidence of Graves' disease after mantle irradiation.     

Hypertrophy and hyperplasia during goitre growth and involution in rats--separate bioeffects of TSH and iodine

Goitre growth was investigated in rats receiving a low iodine diet (less than 0.1 microgram iodine/g) and either 1 g/l KClO4 or 1 g/l propylthiouracil (PTU), or a combination of KClO4 or PTU with 50.82 nmol/1 T3 in tap water for 3 weeks. To investigate goitre involution, rats with iodine-deficient goitres were treated for 3 weeks either with T3 (0.5 microgram T3/day = 0.768 nmol/day), iodide (0.5 or 2.7 micrograms KI/day) or a combination of T3 with both iodide doses. Histology together with total DNA distinguished between hypertrophy and hyperplasia of the gland. During goitre growth there was highly significant correlation between goitre weight and TSH serum level (r = 0.93, P less than 0.001). Thyroid total DNA, however, was only weakly correlated to TSH but was inversely related to the degree of iodine deficiency. During goitre regression, TSH levels were normalized, histological signs of hypertrophy had disappeared, and thyroid weight was nearly normalized in all therapy groups. Total DNA, however, was normalized only with 2.7 micrograms KI/day (95 +/- 18 micrograms DNA/gland), and still elevated in all other groups. The highest DNA levels were found under T3 therapy (143 +/- 21 micrograms DNA/gland) and under 0.5 microgram KI/day (161 +/- 19 micrograms DNA/gland). Reduction of total DNA was independent of TSH, but followed replenishment of the iodine content of the glands. We conclude that TSH mainly induces hypertrophy, whereas thyroid hyperplasia is mainly regulated by the intracellular iodine content.     

TSH secretion in Cushing's syndrome: relation to glucocorticoid excess, diabetes, goitre, and the 'sick euthyroid syndrome'

Thyrotrophin (TSH) secretion was studied in 63 patients with Cushing's syndrome (53 patients with pituitary dependent Cushing's disease, eight with adrenocortical tumours, and two with the ectopic ACTH syndrome). Prior to treatment, TSH response to 200 micrograms of TRH intravenously was significantly decreased compared to controls; TSH response was 'flat' (increment less than 2 mU/l) in 34 patients (54%). Patients with a flat response to TRH had significantly higher morning and midnight cortisol levels than patients with a TSH response of 2 mU/l and more; this was not due to differences in serum thyroid hormone levels. Basal TSH, TSH increment after TRH, and stimulated TSH value, but not serum triiodothyronine, were correlated with cortisol measurements (0800 h serum cortisol, midnight cortisol, and urinary free corticoid excretion). After exclusion of 40 patients with additional disease (severe systemic disease, diabetes mellitus, or goitre), cortisol-TSH correlations were even more pronounced (r = -0.73 for midnight cortisol and stimulated TSH levels), while in the patients with additional complications, these correlations were slight or absent. Successful treatment in 20 patients was associated with a rise in thyroid hormone levels and the TSH response to TRH. These results indicate that (1) the corticoid excess but not serum T3 is the principal factor regulating TSH secretion in Cushing's syndrome, (2) a totally flat response to TRH is rare, and (3) TSH suppression and lower than normal serum thyroid hormone levels are reversible after treatment. Since factors like severe systemic disease, diabetes mellitus and goitre also affect TSH secretion, they tend to obscure the statistically significant correlations between cortisol excess and TSH secretion.     

Goitre Survey in Armidale and the New England Region

The results of a goitre survey in school children in the New England Region are presented and compared with previous studies. Goitre incidence has fallen significantly in Tamworth but has remained unchanged in Armidale. Analyses of blood and urine showed no differences in thyroid hormone levels, TSH, and urinary iodide in goitre and non-goitre subjects. In one group of goitre subjects prolactin levels were found to be significantly higher than those in a non-goitre group matched for sex, age and years in the district. The estimated iodine intake was well above normal requirements in all age groups studied. Sources of dietary iodine in the New England Region are outlined with special reference to milk and water. A brief review of clinical thyroid disease in Armidale is presented and reveals an unusually high incidence of both hyper- and hypo-thyroidism.     

Oral prednisolone supplement abolishes the acute adverse effects following initiation of depot bromocriptine therapy

OBJECTIVE We measured pyridinium cross-links, markers of bone resorption, by an enzyme-linked immunosorbent assay (ELISA) in hypothyroid patients to see whether bone resorption was reduced in hypothyroidism and whether it increased with T4 treatment. DESIGN AND PATIENTS Eight hypothyroid patients, whose initial TSH levels were 268.1 ± 87.7 mU/l (mean ± SE), were treated with T4 (100μg/day). Urinary excretion of pyridinium cross-links was assayed before and after T4 treatment. MEASUREMENTS Pyrilinks and Pyrilinks-D kits were used. The Pyrilinks assay measures free forms of pyridinoline and deoxypyridinoline together (PYD), while the Pyrilinks-D assay measures deoxypyridinoline (DPD) alone. The Pyrilinks reference ranges for normal subjects are 8–24nmol/mmol creatinine in males and 10–28nmol/mmol creatinine in normal premenopausal females. The DPD reference ranges obtained from normal men and women aged 40–50 years were 3.20 ± 0.75 (mean ± SD) nmol/mmol creatinine and 4.55 ± 1.22 nmol/mmol creatinine, respectively. RESULTS The sensitivity of the assay was enhanced by simply using less diluted urine samples. Concentrations of both compounds of the urinary pyridinium cross-links were low in untreated hypothyroid patients and increased gradually as thyroid hormone status improved from hypothyroidism to euthyroidism. One month after treatment when the TSH levels in the patients were still as high as 74.4 ± 44.5 mU/l, urinary PYD excretion has increased to 2.6 times the pretreatment level. When the TSH levels of the patients decreased below 10 mU/l, both PYD and DPD increased significantly to 3.8 and 3.3 times pretreatment values, respectively. CONCLUSIONS Although hyperthyroidism or excess treatment with thyroid hormone has been known to induce bone resorption, this is the first report that urinary excretion of pyridinium cross-links is reduced in hypothyroidism and is normalized by physiological thyroid hormone replacement.     

Appearance of thyroid stimulating antibody and Graves' disease after radioiodine therapy for toxic nodular goitre

A patient with toxic nodular goitre is described in whom radioiodine (¹³¹I) therapy paradoxically induced typical Graves' disease. This patient had a goitre with two autonomously functioning nodules suppressing uptake by the remainder of the gland. Circulating thyroid peroxidase antibody indicated the coexistence of focal lymphocytic thyroiditis. Radioiodine therapy was followed by the development of severe and persistent Graves' hyperthyroidism associated with diffuse ¹³¹I uptake by the gland. A second administration of ¹³¹I produced a further worsening of hyperthyroidism, and the appearance of ophthalmopathy. TSH-receptor antibody and thyroid stimulating antibody were undetectable before ¹³¹I, appeared after the first administration of radioiodine, and showed a further increase after the second dose of ¹³¹I. We suggest that, in a patient genetically susceptible to thyroid autoimmunity, the release of TSH-receptor antigenic components from follicular cells damaged by radioiodine therapy triggered an autoimmune response to the TSH-receptor, thus turning a toxic nodular goitre into Graves' disease.     

TRANSIENT THYROTOXICOSIS IN ENDEMIC GOITRE PATIENTS FOLLOWING EXPOSURE TO A NORMAL IODINE INTAKE

Twenty-three endemic goitrous subjects (goitre grade: III and IV) that were living in a chronic iodine-deficient area (iodine intake: less than 40 μg I/d) were submitted to clinical and laboratory evaluation within 3–8 weeks of arrival at the metropolitan area of São Paulo, where daily iodine intake is estimated to be 150–200 μg I/d. Eight patients developed a mild thyrotoxic state (T4 = 14.7 ± 2.3 μg/dl, T3 = 279 ± 55 ng/dl, no TSH response to TRH). Five additional subjects, although euthyroid, had a blunted TSH-response to TRH, and the remaining ten patients were euthyroid and had a normal TSH response to TRH. Thyrotoxicosis was associated with larger goitres (mean thyroid weight: 133 ± 46 g), with high thyroid uptake of RAI (mean 24 h ¹³¹ I uptake: 40 ± 15%) but not with increased urinary iodine excretion. Serum Tg levels were more elevated in the first two groups of patients (respectively, geometric means 68 and 72 ng/ml), than in the euthyroid, TRH-responsive group (52 ng/ml). Thyrotoxicosis resolved spontaneously after three to six months without the need for any specific medication. It was concluded that a relatively small and normal iodide intake due to regular consumption of iodized salt and industrialized foods may induce a transient form of thyrotoxicosis in endemic goitre patients arriving into urban areas.