Thyroid hormone resistance: the role of mutational analysis.

The finding of increased thyroxine (T4) and tri-iodothyronine (T3) levels in a patient with normal or increased thyroid-stimulating hormone is unexpected and presents a differential diagnosis between a thyroid-stimulating hormone-secreting pituitary adenoma, generalized resistance to thyroid hormone (RTH) and laboratory artefact. Without careful clinical and biochemical evaluation, errors may occur in patient diagnosis and treatment. In the case of RTH, mutation of the thyroid hormone receptor beta gene results in generalized tissue resistance to thyroid hormone. As the pituitary gland shares in this tissue resistance, euthyroidism with a normal thyroid-stimulating hormone is usually maintained by increased thyroid hormones. To date, we have identified eight pedigrees in New Zealand with mutations in the thyroid hormone receptor beta gene, including two novel mutations. Mutational analysis of the thyroid hormone receptor beta gene allows definitive diagnosis of RTH, potentially avoiding the need for protracted and expensive pituitary function testing and imaging. Mutational analysis also enables family screening and may help to avoid potential misdiagnosis and inappropriate treatment.

Low serum triiodothyronine (T3) and hypothyroidism in anorexia nervosa.

Measurements of serum thyroid hormones were compared in 22 patients with typical anorexia nervosa and 22 euthyroid control subjects. Serum total triiodothyronine (T3) was (mean +/- (SE) 62.1 +/- 7.1 ng/100 ml in anorexia patients and 115.2 +/- 8.4 ng/100 ml in control subjects (P less than 0.001). Serum adjusted thyroxine (T4Adj) was significantly different in the anorexia (7.1 +/- 0.4) and control (8.2 +/- 0.4) groups. Serum T3 was subnormal in 63% and T4Adj subnormal in 36% of the 22 anorexia patients. The mean serum T4/T3 in anorexia patients (158 +/- 19) was higher than that in the control subjects (88 +/- 5.5, P less than 0.005) or in 18 patients with hypothalamic or pituitary hypothyroidism (77.9 +/- 10.1, P less than 0.001). Following weight gain in 6 anorexia patients, there was a significant rise in serum T3 without change in T4Adj concentration. The Achilles reflex half-relaxation time (ART) in 38 anorexia patients was 348.6 +/- 10 msec compared with 280 +/- 30 msec in 168 normal age-matched subjects (P less than 0.001), and was prolonged (greater than 340 msec) in 65% of these 38 patients. In 18 anorexia patients with measured ART, T3 and T4Adj, the mean ART was longer 376.1 +/- 20 msec) in 10 with subnormal T3 than in 8 patients with a normal T3 (294.7 +/- 13.2 msec, P less than 0.01). There was no significant difference in the mean ART between patients with a normal or low serum T4Adj. Administeration of oral T3 40 mug/day for 4 weeks to 11 anorexia patients caused a significant reduction (P less than 0.001) in mean ART of 108.7 +/- 9.6 msec compared with 17.7 +/- 3.3 msec in 18 normal subjects. There was a normal peak serum TSH and a rise in mean total serum T3 of 47 +/- 12 ng/100 ml (range 11-100 ng/ml) in 7 of 8 patients following 200 mug of iv thyrotropin releasing hormone (TRH). The fall in serum TSH was delayed in 6 patients. Assessment of hypothalamic control of thyroid function in 3 patients using the method of thyroidal iodide release (TIR) showed impairment of the normal diurnal variation and response to administered glucocorticoids. In the absence of a space-occupying pituitary lesion, the TRH and TIR data suggest a central inhibition of thyroid function, possibly by impairment of hypothalamic TRH release. In addition, a probable decrease of peripheral T4 to T3 conversion leads to low serum T3 concentrations. The prolonged basal ART and the marked ART reduction in response to T3 administration is attributed to correction of tissue thyroid hormone deficiency in the anorexia patients.

The acute thyroidal response to iodixed oil in severe endemic goiter.

The acute changes in serum thyrotropin (TSH) triiodothyronine (T3) and thyroxine (T4), were measured in 14 subjects, 4 to 10 (mean = 6) days following intramuscular iodized oil injection. In 8 subjects with small or absent goiter there was a significant fall in T3 and a rise in TSH concentrations, suggesting an acute inhibitory effect of the iodine. In 6 subjects with large multinodular goiters there was a marked rise in both T3 and T4, and reduction in the elevated basal TSH. Biochemical hyperthyroidism occurred in 3 of these subjects. The acute thyroid hormone response to iodized oil, whether inhibitory or stimulatory in a particular subject, depends both on goiter size and on the serum concentration of TSH.

Failure of triiodothyronine to inhibit TSH-mediated thyroid hormone release in man.

We studied the effect of short-term triiodothyronine administration on thyroid gland responsivity to exogenous thyrotropin in four euthyroid human subjects. Thyroidal iodine release and serum thyroxine during daily im injections of bovine TSH were not significantly inhibited, despite a four-fold elevation in serum T3 concentrations. This negative finding contrasts with earlier positive reports of a regulatory "short-loop" effect of elevated circulating T3 on the thyroid gland. This difference may be due either to the use in previous murine or in vitro studies of non-physiologic, high doses of exogenous T3, or failure to control the withdrawal of the trophic effect of endogenous TSH in man on the subsequent glandular response.

Lack of indomethacin effect on thyroid function in man.

Administration of indomethacin 200 mg daily for 2 days to four euthyroid volunteers was without significant effect on serum triiodothyronine or thyroxine and caused no cinsistent alteration of serum TSH. There were minor and variable changes in the pattern of thyroidal iodine release (TIR) in these euthyroid subjects. In one subject both the TIR pattern and serum TSH concentration were altered in the same direction, suggesting that these minor changes were of central origin. Indomethacin also had no effect on the stimulated pattern of TIR in one euthyroid subject receiving daily exogenous TSH injections, or in a patient with untreated hyperthyroid Graves' disease. Prostaglandin A1 infusion in one subject did not alter serum TSH or thyroidal iodine release. It is concluded that prostaglandins probably have no obligatory physiological role in modulating TSH or thyroid hormone secretion in man.

Urinary immunoprecipitation method for estimation of thyroxine to triiodothyronine conversion in altered thyroid states.

A new method is described for the estimation of T4 to T3 conversion in man and is applied to the study of hyperthyroid and hypothyroid clinical states. The method employs simultaneous iv injection of [125I]T4 and [131I]T3 with isolation of the labeled T3 tracers in 4- to 8-day pooled urine samples by a combination of solvent extraction, desalting, and immunoprecipitation procedures. Using [131I]T3 as a recovery standard, the T4 to T3 conversion ratio was found to be 0.470 +/- 0.011 in euthyroid subjects. This confirmed our earlier findings of 0.482 +/- 0.014 using a paper chromatographic method and nonsimultaneous isotope administration. The conversion ratio was increased in hypothyroidism to 0.535 +/- 0.011 (P less than 0.02) and decreased in hyperthyroidism to 0.415 +/- 0.009 (P less than 0.01). These changes parallel the fraction of the radioiodine collected in the urine for both T4 and T3; normal values are 77 +/- 4% for T4 and 76 +/- 4% for T3, values in hypothyroidism are 79 +/- 1% for T4 and 79 +/- 3% for T3, and values in hyperthyroidism are 58 +/- 3% for T4 and 58 +/- 5% for T3 (P less than 0.01). These findings indicate that 1) urinary T4 to T3 conversion values are highly reproducible in euthyroid as well as hyperthyroid and hypothyroid states; 2) the reduction in T4 to T3 conversion in hyperthyroidism probably reflects increased T4 disposal by nondeiodinative pathways and possibly the reverse in hypothyroid states; and 3) since urinary T4 to T3 conversion values in euthyroid subjects exceeded all reported conversion values in blood, there may be an alternate pathway of T3 production and disposal which is not reflected in the blood T3 production rate.

A novel variant of transthyretin (prealbumin), Thr119 to Met, associated with increased thyroxine binding.

A group of patients with prealbumin associated hyperthyroxinemia possess a common single base substitution in the fourth exon of their transthyretin gene. This cytosine to thymine substitution occurs in the codon for residue 119 and results in the predicted replacement of a threonine residue with a methionine at this position. A new NcoI restriction endonuclease cleavage site is created by the point mutation and can be detected by a rapid and simple assay based on the polymerase chain reaction. This variant transthyretin is inherited in an autosomal dominant manner and is apparently not amyloidogenic but is associated with increased thyroxine binding. As healthy heterozygous individuals have normal serum thyroxine concentrations, the hyperthyroxinemia sometimes found may not be primarily due to the variant.

Zoladex treatment of symptomatic prostatic carcinoma.

The depot LH-RH agonist Zoladex was used to treat 38 patients with previously untreated symptomatic stage D2 prostate carcinoma. Side effects were minimal and patient acceptability excellent, although temporary tumor flare occurred in 11% of patients. Eighty-four percent experienced subjective improvement and 87% had objective evidence of initial disease stabilization or remission lasting 3 months. Serum levels of gonadotrophin and free testosterone as well as androgens of adrenal origin fell significantly with treatment. Long-term survival to date appears at least as good as that described for conventional endocrine therapy.

A clinico-pathological study of 100 patients with solitary 'cold' thyroid nodules.

One hundred consecutive patients were studied at the Auckland Hospital thyroid clinic over a two year period 1974 to 1976, who subsequently had surgical excision of a solitary cold nodule. Thyroid carcinoma was present in 17 percent, adenoma in 44 percent, colloid nodules in 25 percent and a thyroid cyst in 14 percent. Although thyroid neoplasms were significantly more frequent in patients under 40, other clinical or scan features analysed were not predictive of carcinoma or neoplasm.

A clinico-pathological study of two patients with Cushing's disease.

The clinical and autopsy findings are described in two patients with Crushing's disease who died five days and 18 years following bilateral adrenalectomy. In each case tomography of the pituitary fossa was normal but examination of the pituitary revealed a 5 to 6 mm basophilic adenoma in the antero-inferior aspect of the gland. The first patient failed to show suppression of urinary oxogenic steroids during administration of high dose dexamethasone. The second patient had functioning adrenal autografts in skeletal muscle 18 years after adrenalectomy. The clinico-pathological correlation of these two patients supports modern re-emphasis on the aetiology of Cushing's disease as a primary pituitary tumour and its treatment by selective trans-sphenoidal hypophysectomy.

Subclinical hypothyroidism.

Clinical and biochemical indices of thyroid function were compared in 18 euthyroid control subjects and 54 patients at risk of developing hypothyroidism, and the assessment repeated after a four-week trial of oral triiodothyronine (T3) 40 microgram daily. Patients with minor elevation of the pre-treatment serum TSH concentration (5-15 microU/ml) showed significant reduction in the free thyroxine index (FTI), prolongation of the basal ankle reflex half-relasation time (ART), and shortening of the ART after oral T3 treatment, when compared either to control subjects or to patients with a normal TSH level. It is concluded that patients with minimal TSH elevation have minor but parallel abnormalities of both thyroid hormone concentration and action.

TRH testing, T4-thyrotoxicosis and the aging thyroid gland.

Secondary thyroid function tests were compared in 41 mildly thyrotoxic and 36 euthyroid patients with an elevated free thyroxine index (FT4I). A serum TSH measurement 20 minutes after intravenous TRH (delta TSH) most reliably separates these two groups. A significant delta TSH response (greater than 0.5 microU/ml) is also helpful in excluding clinical thyrotoxicosis in patients with nodular goitre. The free T3 index was normal in one-third of mildly thyrotoxic patients and in all euthyroid patients with a falsely elevated FT4I. Blunted delta TSH responses to TRH in elderly New Zealand women were associated with nodular goitre or occult thyroid nodularity revealed only by thyroid scan. The reduced TRH responses are more likely due to partial thyroid autonomy than reduced synthetic capacity of thyrotrophs in old age.

Iodine intake in an urban environment: a study of urine iodide excretion in Auckland.

Dietary iodine intake was estimated by measurement of iodide in random overnight 12 hr and 24 hr urine samples. Urinary iodide excretion was measured in 231 healthy females comprising 127 female secondary students (ages 16-19), 27 female tertiary students (17-23 yr), 42 female laundry workers (18-52 yr) and 26 pregnant women in the third trimester (18-40 yr). Urine iodide excretion was also examined in a group of 28 patients attending a thyroid clinic, with thyroid disease of diverse aetiology and in 34 patients taking the antiarrhythmic drug amiodarone for control of cardiac arrhythmias. The mean daily urine iodide excretion was 2.4 mumol/day (0.9-5.8 mumol/day) and iodide to creatinine ratio 0.21 mumol/mmol (0.09-0.29). Iodine deficiency (less than 0.4 mumol/day) was not observed in any subject. Excessive iodine (greater than 8 mumol/day) was found only in patients known to be taking iodine-containing drugs and in one normal individual. The urine iodide was normal in 154 female students, 14 of whom had a trivial thyroid enlargement. The study suggests that dietary sources other than iodised salt contribute significantly to dietary iodine intake and that residual goitre in the community is not secondary to deficiency or excess of dietary iodine.

Addison's disease, adrenal autoantibodies and computerised adrenal tomography.

The present study describes 53 patients with Addison's disease, who attended Auckland hospitals between 1971-1980, 32 of whom presented for the first time during this period, when the mean annual incidence of Addison's disease was 4.5 cases/million population, and the respective frequency of idiopathic (auto-immune) and tuberculous aetiologies was 92 percent and 4 percent for caucasians, but 25 percent and 63 percent for Polynesians. In addition, adrenal reserve was tested by ACTH stimulation in 20 clinically non-Addisonian patients in whom circulating adrenal antibodies had been incidentally demonstrated and present for periods of up to six years, and was normal in all cases. Such antibodies therefore lack functional disease specificity. The diagnostic value of CT adrenal scanning in illustrating the contrasting appearances between tuberculous and auto-immune adrenalitis is shown in four patients.

Disopyramide-induced hypoglycaemia and increased serum insulin.

A patient treated with disopyramide presented with hypoglycaemia, a raised serum insulin level and died of pneumonia. From these findings and a review of 10 case reports, we propose that disopyramide causes hypoglycaemia by stimulation of insulin release as described for the antimalarial drugs quinine and quinidine.

Goitre and thyroid dysfunction during chronic amiodarone treatment.

We measured thyroid function in a cross-sectional survey of 37 unselected patients receiving chronic amiodarone treatment. Palpable goitre was presented in 17 patients and was a new finding in ten. Despite frequent elevations of serum free T4 (67%) or free T4 index (43%), all 37 patients were clinically euthyroid with a normal or decreased serum free T3 or free T3 index. Mean urine iodide/creatinine excretion was increased 13-fold. Three patterns of thyroid function were seen; in 21 patients with normal TRH responses, the mean basal serum TSH was significantly elevated. Five patients had biochemical hypothyroidism which did not require treatment. Eleven patients had evidence of thyroid autonomy and the three patients with absent TRH responses each gave a past history of goitre or thyrotoxicosis; a trial of carbimazole treatment in these three was without clinical benefit. The observed spectrum of subclinical goitre and thyroid dysfunction may result from an unpredictable thyroid response to excessive free iodide combined with a weak goitrogenic effect of amiodarone mediated by increased TSH secretion.