Risk of Thyroid Cancer Among Solid Organ Transplant Recipients.

Solid organ transplant recipients have an elevated incidence of thyroid cancer. We evaluated a wide range of potential risk factors in a cohort of 229 300 U.S. solid organ transplant recipients linked with 15 stage/regional cancer registries (1987-2012). Incidence rate ratios (IRRs) were adjusted for age, sex, race/ethnicity, transplanted organ, year of transplantation, and time since transplantation. Hazard ratios (HRs) for death and/or graft failure were adjusted for age, sex, race/ethnicity, transplanted organ, and year of transplantation. After transplantation, 356 thyroid cancers were diagnosed. Thyroid cancer incidence was 2.50-fold higher in transplant recipients than the general population (95% confidence interval [CI] 2.25-2.77). Among recipients of different organs, kidney recipients had the highest incidence of thyroid cancer (IRR = 1.26, 95% CI 1.03-1.53). Elevated thyroid cancer incidence was associated with cholestatic liver disease/cirrhosis as an indication for liver transplantation (IRR = 1.69, 95% CI 1.09-2.63), hypertensive nephrosclerosis as an indication for kidney transplantation (IRR = 1.41, 95% CI 1.03-1.94), and longer prior dialysis among kidney recipients (5+ vs. <1 year, IRR = 1.92, 95% CI 1.32-2.80; p-trend <0.01). Posttransplantation diagnosis of thyroid cancer was associated with modestly increased risk of death (HR = 1.33, 95% CI 1.02-1.73). Overall, our results suggest that end-stage organ disease and longer duration of dialysis may contribute to higher thyroid cancer incidence in transplant recipients.

Substrate cycling between gluconeogenesis and glycolysis in euthyroid, hypothyroid, and hyperthyroid man.

Substrate, or futile cycles, have been hypothesized to be under hormonal control, and important in metabolic regulation and thermogenesis. To define the role of thyroid hormones in the regulation of substrate cycling in glycolysis and gluconeogenesis, we measured rates of cycling in normal (n = 4), hypothyroid (n = 5), and hyperthyroid (n = 5) subjects employing a stable isotope turnover technique. Glucose labeled with deuterium at different positions (2-D1-, 3-D1-, and 6,6-D2-glucose) was given as a primed-constant infusion in tracer doses, and arterialized plasma samples were obtained and analyzed by gas-chromatography mass-spectrometry for the steady state enrichment of glucose that was labeled at the various positions. The rate of appearance (Ra) was then calculated for each isotopic tracer. The difference between the Ra determined by 2-D1-glucose (Ra2) and the Ra determined by 3-D1-glucose (Ra3) represents the substrate cycling rate (SCR) between glucose and glucose-6-phosphate. The difference between the Ra determined by 3-D1-glucose (Ra3) and the Ra determined by 6,6-D2-glucose (Ra6) represents the SCR between fructose-6-phosphate and fructose-1,6-diphosphate. The difference between Ra2 and Ra6 represents the combined SCR of both cycles. In normal subjects (serum thyroxine [T4] = 8.4 +/- 1.2 microgram/dl (all expressions, mean +/- SD), n = 4), the rates of appearance for Ra2, Ra3, and Ra6 were 3.23 +/- 0.56, 2.64 +/- 0.50, and 2.00 +/- 0.27 mg/kg X min, respectively, whereas those in the hypothyroid subjects (T4 = 1.0 +/- 0.8 microgram/dl; n = 5) were 1.77 +/- 0.56 (P less than 0.01), 1.52, 1.57 +/- 0.31 (P less than 0.05) mg/kg X min, respectively. Conversely, the rates of appearance for Ra2 and Ra6 in the hyperthyroid subjects (T4 = 23.9 +/- 3.6 micrograms/dl) were 3.94 +/- 0.43 (P less than 0.05) and 2.54 +/- 0.22 (P less than 0.02), respectively, compared with the normal subjects. On the basis of these data, we noted that the normal subjects had a combined SCR of 1.23 +/- 0.35 mg/kg X min. In contrast, the hypothyroid patients had a significantly decreased combined SCR, 0.20 +/- 0.54 mg/kg X min (P less than 0.02). The hyperthyroid patients had a combined SCR of 1.39 +/- 0.23 mg/kg X min (P less than NS). To determine whether these cycles responded to thyroid hormone treatment, these same hypothyroid subjects were acutely treated for 1 wk with parenteral 50 micrograms/d sodium L-triiodothyronine and chronically with 100-150 micrograms/d L-thyroxine. After 7 d, their mean oxygen consumption rate and carbon dioxide production rate increased significantly from 102+/-13 micromol/kg.min, to 147+/-34 micromol/kg.min (P<0.05), and from 76+/-13 micromol/kg.min to 111+/-19 micromol/kg.min (P<0.05), respectively. The combined SCR (Ra(2)--Ra(6) remained unchanged at 0.07+/-0.37 mg/kg.min. However, after 6 mo of oral L-thyroxine therapy (T(4)=9.5+/-1.4 microgram/kl) the treated hypothyroid patients had increased their combined SCR (Ra(2)--Ra(6)) to 0.86 +/-0.23 mg/kg.min (P<0.02), a value not significantly different from the combined SCR of normal subjects. We conclude that substrate cycling between glucose and glucose-6-phosphate and between fructose-6-phosphate and fructose-1,6-diphosphate occurs in man and is affected by thyroid hormone. Substrate cycles may represent a mechanism by which thyroid hormone alters the sensitivity of certain reactions to metabolic signals.

Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study.

CONTEXT: After surgery for differentiated thyroid carcinoma, many patients are treated with radioiodine to ablate remnant thyroid tissue. This procedure has been performed with the patient in the hypothyroid state to promote endogenous TSH stimulation and is often associated with hypothyroid symptoms and impaired quality of life. OBJECTIVE AND INTERVENTION: This international, randomized, controlled, multicenter trial aimed to compare the efficacy and safety of recombinant human TSH (rhTSH) to prepare euthyroid patients on L-thyroxine therapy (euthyroid group) to ablate remnant thyroid tissue with 3.7 GBq (100 mCi) 131I, compared with that with conventional remnant ablation performed in the hypothyroid state (hypothyroid group). Quality of life was determined at the time of randomization and ablation. After the administration of the 131-I dose, the rate of radiation clearance from blood, thyroid remnant, and whole body was measured. RESULTS: The predefined primary criterion for successful ablation was "no visible uptake in the thyroid bed, or if visible, fractional uptake less than 0.1%" on neck scans performed 8 months after therapy and was satisfied in 100% of patients in both groups. A secondary criterion for ablation, an rhTSH-stimulated serum thyroglobulin concentration less than 2 ng/ml, was fulfilled by 23 of 24 (96%) euthyroid patients and 18 of 21 (86%) hypothyroid patients (P = 0.2341). Quality of life was well preserved in the euthyroid group, compared with the hypothyroid group, as demonstrated by their lower pretreatment scores on the Billewicz scale for hypothyroid signs and symptoms, 27 +/- 7 vs. 18 +/- 4 (P < 0.0001) and their significantly higher Short Form-36 Health Assessment Scale scores in five of eight categories. Euthyroid patients had a statistically significant one third lower radiation dose to the blood, compared with patients in the hypothyroid group. CONCLUSIONS: This study demonstrates comparable remnant ablation rates in patients prepared for 131I remnant ablation with 3.7 GBq by either administering rhTSH or withholding thyroid hormone. rhTSH-prepared patients maintained a higher quality of life and received less radiation exposure to the blood.

Subclinical thyroid dysfunction in the elderly.

Subclinical thyroid dysfunction is more common in older persons. By definition, these disorders are recognized by isolated elevation or suppression of the serum TSH concentration, in association with a normal serum free thyroxine level. Among individuals over 65 years old, subclinical hypothyroidism is found in approximately 10% of women and approximately 3% of men. It is most commonly due to autoimmune thyroiditis or previous treatment for hyperthyroidism. There may be three indications for L-thyroxine therapy: (a) presence of antithyroid antibodies, indicating substantial risk of progression to over hypothyroidism; (b) symptoms consistent with thyroid hormone deficiency; and (c) an elevated serum LDL-cholesterol. Subclinical hyperthyroidism is present in approximately 1%-2% of older persons. The most common cause is excessive thyroid hormone therapy, followed by mild endogenous hyperthyroidism due to Graves' disease or nodular goiter. These can be differentiated from other causes of low serum TSH concentration based on clinical and other laboratory and radionuclide scan criteria. The most serious consequences of subclinical hyperthyroidism are atrial fibrillation and osteoporosis, to which elderly patients are particularly predisposed.

Pseudotumor cerebri and hypothyroidism.

A 38-year-old obese woman with concurrent hypothyroidism and pseudotumor cerebri was monitored with serial thyroid function tests and CSF pressure determinations during levothyroxine sodium replacement therapy. Following normalization of the patient's thyroid status, assessed by both clinical and chemical indexes (serum thyroxine level, 1.5 to 11.0 micrograms/dL; serum thyrotropin level, 128 to 1.5 micro units/mL), intracranial hypertension persisted for more than four months. After weight loss, acetazolamide therapy, and intermittent CSF drainage failed to produce remission, glucocorticoid therapy was associated with prompt, sustained resolution of the pseudotumor cerebri. Contrary to previous reports, this patient's clinical course suggests that thyroid hormone deficiency and pseudotumor cerebri are not causally related.

Sequestered substernal goiter.

A young woman with a normally located and only subtly nodular thyroid gland in the neck was found to have a clinically distinct and radioisotopically "cold" anterior mediastinal mass, which proved to be a benign colloid adenoma. While this constellation of findings usually suggests the presence of a nonthyroidal neoplasm, eg, lymphoma, thymoma, or teratoma, our case illustrates that sequestered benign nodular goiter should also be considered in the differential diagnosis. Clinical clues, such as a nodular thyroid gland, movement of the mass with deglutition, and a family history of nodular goiter, should suggest this possibility. A characteristic computed tomographic appearance may also prove useful in recognition of this rare disorder.

American Thyroid Association guidelines for detection of thyroid dysfunction.

OBJECTIVE: To define the optimal approach to identify patients with thyroid dysfunction. PARTICIPANTS: The 8-member Standards of Care Committee of the American Thyroid Association prepared a draft, which was reviewed by the association's 780 members, 50 of whom responded with suggested revisions. EVIDENCE: Relevant published studies were identified through MEDLINE and the association membership's personal resources. CONSENSUS PROCESS: Consensus was reached at group meetings. The first draft was prepared by a single author (P.W.L.) after group discussion. Suggested revisions were incorporated after consideration by the committee. CONCLUSIONS: The American Thyroid Association recommends that adults be screened for thyroid dysfunction by measurement of the serum thyrotropin concentration, beginning at age 35 years and every 5 years thereafter. The indication for screening is particularly compelling in women, but it can also be justified in men as a relatively cost-effective measure in the context of the periodic health examination. Individuals with symptoms and signs potentially attributable to thyroid dysfunction and those with risk factors for its development may require more frequent serum thyrotropin testing.

Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association.

A set of minimum clinical guidelines for use by primary care physicians in the evaluation and management of patients with thyroid nodules or thyroid cancer was developed by consensus by an 11-member Standards of Care Committee (the authors of the article) of the American Thyroid Association, New York, NY. The participants were selected by the committee chairman and by the president of the American Thyroid Association based on their clinical experience. The committee members represented different geographic areas within the United States, to reflect different practice patterns. The guidelines were developed based on the expert opinion of the committee participants, as well as on previously published information. Each committee participant was initially assigned to write a section of the document and to submit it to the committee chairman, who revised and assembled the sections into a complete draft document, which was then circulated among all committee members for further revision. Several of the committee members further revised and refined the document, which was then submitted to the entire membership of the American Thyroid Association for written comments and suggestions, many of which were incorporated into a final draft document, which was reviewed and approved by the Executive Council of the American Thyroid Association.

Acute L-triiodothyronine administration potentiates inotropic responses to beta-adrenergic stimulation in the isolated perfused rat heart.

OBJECTIVE: Acute inotropic effects of triiodothyronine (T3) have been reported, employing both in vivo experimental animal models and in vitro isolated heart perfusions. However, the mechanisms responsible for these acute inotropic effects remain unclear. The aim of this study, therefore, was to delineate the role of the beta-adrenergic receptor system in these acute responses. METHODS: The hearts from both euthyroid and hypothyroid (treated with 0.05% PTU in drinking water) male Sprague-Dawley rats were used in 5 experimental study protocols. Hearts from euthyroid rats were perfused with buffer containing either T3(10(-7) M) or control while continuously recording left ventricular function for 10 min ('acute effects'). Two-hour perfusions ('subacute effects') and cardiac responses following increasing doses of isoproterenol (10(-10) to 10(-6) M) in the presence or absence of T3-containing buffer (acute interaction) were also determined. In hypothyroid rats, the subacute responses and the acute interactions were investigated. RESULTS: In the presence of T3, an acute, significant potentiation of the inotropic responses following beta-adrenergic stimulation with isoproterenol was observed in both rat cohorts, which was more pronounced in hearts from euthyroid rats. An acute (< 40 s), but transient (79 +/- 8 s), direct inotropic response was observed in hearts from euthyroid rats. No cardiac responses were seen during a 2-h perfusion in hearts from either euthyroid or hypothyroid rats. CONCLUSIONS: The acute inotropic effects of T3 in non-ischemic myocardium probably result from an acute interaction between T3 and catecholamines rather than through a direct inotropic effect of T3 alone.

Controversies in the follow-up and management of well-differentiated thyroid cancer.

Thyroid cancer is a common malignancy with an apparent increasing incidence and a wide spectrum of clinical behavior and therapeutic responsiveness. Recent advances in diagnosis, primary treatment, and long-term monitoring have led to enhanced detection of primary and recurrent disease and improvements in therapy. Controversy still surrounds several issues: the most accurate predictive staging system and histological subclassification scheme, optimal preoperative assessment and surgical extent, appropriate use of radioiodine for remnant ablation, goal for thyrotropin-suppressive thyroid hormone therapy, best practices in immediate postoperative and long-term monitoring, and approach to the patient with thyroglobulin evidence of residual disease. In this paper, recent data related to these controversial issues are critically reviewed.

Modulation of atrial natriuretic factor by thyroid hormone: messenger ribonucleic acid and peptide levels in hypothyroid, euthyroid, and hyperthyroid rat atria and ventricles.

The effect of thyroid hormone on atrial natriuretic factor (ANF) production was investigated in hypothyroid, euthyroid, and hyperthyroid rats by measuring levels of ANF mRNA and ANF in myocardium. ANF mRNA was quantitated by dot blot hybridization, and ANF by specific RIA. Relative ANF mRNA concentrations (ANF mRNA to 18S RNA) were determined for right atria, left atria, and ventricular apices. The total chamber content of ANF mRNA was estimated (concentration X total chamber RNA) and used as a measure of each tissue's synthetic capacity. For both atrial tissues, ANF mRNA contents were significantly higher in hyperthyroidism. In right atria, mean ANF mRNA contents in hypothyroidism and hyperthyroidism were 41% and 176%, respectively, of that in euthyroidism (P less than 0.05, by analysis of variance). Left atrial ANF mRNA contents in hypothyroidism and hyperthyroidism were 94% and 272%, respectively, of the euthyroid value (P less than 0.05). In contrast, atrial ANF mRNA concentrations did not differ significantly between thyroid states. In ventricle, ANF mRNA content and concentration were both correlated with serum T4 concentration. Ventricular ANF mRNA contents in hypothyroidism and hyperthyroidism were 31% and 178%, respectively, of that in euthyroidism (P less than 0.02). The concentration of ventricular ANF mRNA was also significantly increased in hyperthyroidism (P less than 0.05). Tissue content of ANF increased in the hyperthyroid right atria and decreased in the hyperthyroid left atria and ventricles. These observations suggest that increased ANF production by both atria and, to a lesser extent, by the ventricles contributes to the higher circulating ANF levels reported in hyperthyroidism. Furthermore, hyperthyroidism is associated with a specific increase in ventricular ANF mRNA expression as has been observed in other conditions causing ventricular hypertrophy.

Angiotensin II and atrial natriuretic factor-binding sites in various tissues in hypertension: comparative receptor localization and changes in different hypertension models in the rat.

The peptides angiotensin II (ANGII) and atrial natriuretic factor (ANF) regulate blood pressure and salt and water balance by producing antagonistic physiological effects in a variety of tissues. We used in vitro autoradiography with [125I] ANGII and [125I]ANF to compare receptor regulation for both peptides in various tissues in three experimental models of hypertension [two-kidney, one-clip (2K-1C); one-kidney, one-clip (1K-1C); desoxycorticosterone-salt (DOCA-SALT)] and three nonhypertensive control groups [two-kidney (2K-CON); one-kidney (1K-CON); salt-loaded (SALT-CON)]. Blood pressures at death were significantly higher in all three hypertensive groups compared to those in normotensive controls, but there were no significant differences among the hypertensive or normotensive groups, respectively. PRA was highest in the 2K-1C group and lowest in the DOCA-SALT and SALT-CON groups, but plasma ANF levels did not differ significantly among the hypertensive or normotensive groups. In the aorta, ANGII receptor binding was decreased in 2K-1C rats and increased in DOCA-SALT and SALT-CON rats; ANF receptor binding was moderately increased in all three hypertensive groups. Adrenal zona glomerulosa binding for ANGII was highest in the 2K-1C group and lowest in DOCA-SALT rats, while ANF binding was decreased in DOCA-SALT and SALT-CON animals. ANGII renal glomerular binding was increased in DOCA-SALT and SALT-CON groups, and ANF glomerular binding was decreased in the same two groups. In the brain, the subfornical organ showed increased binding for both ANGII and ANF in DOCA-SALT rats. Our results show that tissue receptor binding of ANGII and ANF is regulated in distinct patterns in different models of hypertension, and that these patterns are tissue specific and more complex than simple reciprocal regulation.

Diagnostic accuracy of 131I scanning with recombinant human thyrotropin versus thyroid hormone withdrawal in a patient with metastatic thyroid carcinoma and hypopituitarism.

The diagnostic and therapeutic use of radioactive iodine in patients with thyroid cancer requires a sufficient serum concentration of thyrotropin (TSH) for efficient thyroid tissue uptake of radioiodine. Recombinant human TSH (rhTSH) is a promising new agent, which appears to facilitate radioiodine scanning with similar efficacy to thyroid hormone withdrawal without the immunologic side-effects of bovine TSH (bTSH) administration. Patients with thyroid cancer and concomitant secondary hypothyroidism are particularly difficult to treat because of their inability to elevate endogenous TSH and the limitations of bTSH administration. We describe a patient with metastatic thyroid carcinoma and secondary hypothyroidism with metastases visible only after administration of rhTSH previously unappreciated on thyroid hormone withdrawal scans. This patient exemplifies the usefulness of rhTSH administration before radioactive iodine for this group of patients.

Organ-specific effects of tiratricol: a thyroid hormone analog with hepatic, not pituitary, superagonist effects.

Tiratricol has been used to suppress pituitary TSH secretion, with reported attenuation of extrapituitary thyromimetic effects. A randomized, double-blind trial was performed to define precisely the tissue-specific thyromimetic actions of tiratricol. Ten athyreotic patients, treated for thyroid carcinoma, were randomly assigned to receive L-T4 sodium 0.7 micrograms/kg daily and either tiratricol 10 micrograms/kg or placebo twice daily. The daily dose of L-T4 was increased by 25-50 micrograms increments until the TRH-stimulated TSH level was less than 0.1 mU/L. After measurement of biochemical and physiological parameters of thyroid hormone actions, patients crossed treatment groups. Patients required 46% less L-T4 to achieve equivalent TSH suppression when taking tiratricol. Hepatic effects were enhanced by tiratricol administration, with significant increases in sex hormone binding globulin and ferritin concentrations, 14% and 37%, respectively. Levels of serum cholesterol, LDL cholesterol, and apolipoprotein B were reduced by 7%, 10%, and 13%, respectively, during tiratricol therapy. Triglyceride levels also declined, but there were no changes of high density lipoprotein cholesterol or apolipoproteins AI and AII. Resting metabolic rate, body weight, urea nitrogen excretion, and symptoms did not differ between the two treatment regimens. Cardiovascular function, as reflected by mean arterial pressure and pulse wave arrival time, was not different during tiratricol therapy. Skeletal metabolic activity was affected by tiratricol, with marked elevation of osteocalcin without significant change in serum calcium, PTH, and urinary calcium and hydroxyproline excretion. Tiratricol has increased hepatic and skeletal actions of potential therapeutic value, but does not have enhanced thyromimetic activity specific to the pituitary gland.

Discordant hypothyroxinemia and hypertriiodothyroninemia in treated patients with hyperthyroid Graves' disease.

Hypothyroxinemia and hypertriiodothyroninemia may occur in the course of antithyroid drug or 131I treatment for hyperthyroid Graves' disease. To determine the frequency of combined high serum T3 and low serum T4 concentrations during such treatment and to assess the clinical significance of its recognition, we reviewed 60 patients treated for hyperthyroid Graves' disease with antithyroid drugs (n = 43) or radioactive iodine (n = 17). Six of these patients (10%) were found to have high serum T3 and low serum T4 concentrations during therapy. Four were receiving antithyroid drugs, and 2 had received radioactive iodine. At the time this abnormality occurred, 4 patients were euthyroid, 1 was hypothyroid, and 1 was hyperthyroid. The serum TSH concentration was increased in 2, at the upper limit of normal in 1, and undetectable in 3 patients. In 2 clinically euthyroid patients, these biochemical findings resolved spontaneously. After discontinuation or reduction in the dose of antithyroid drug, clinical and chemical euthyroidism was restored in 2 additional patients with previously elevated TSH levels. In 2 patients, both of whom previously had undetectable serum TSH levels, clinical hyperthyroidism persisted or recurred, and additional therapy was required. No patient developed permanent hypothyroidism during the period of follow-up (1-22 months). An additional 19 of the 60 patients (32%) had an elevated serum T3 level with a normal serum T4 concentration during the course of follow-up. Among these 19 patients, the magnitude of serum T3 elevation was not different between clinically euthyroid (n = 13) and hyperthyroid (n = 6) patients. We conclude that discordance of serum T4 and T3 concentrations is frequently encountered in patients with hyperthyroid Graves' disease during or after therapy. In such patients, the low serum T4 level does not predict hypothyroidism, nor does a high serum T3 level predict hyperthyroidism. Furthermore, the serum T3 concentration in these patients correlates poorly with their clinical thyroid status.

Progesterone has no effect on serum thyroxine-binding globulin concentration in men.

To examine the possible effect of progesterone on circulating T4-binding globulin (TBG) in men, RIA measurements of plasma TBG and T4 levels were made before and after weekly administration of 500 mg medroxyprogesterone acetate, im, to men being treated for paraphilia (sexual deviation syndromes). No change in the mean pretreatment plasma TBG concentration was found after 7-29 days [21.5 +/- 1.2 (+/- SEM) to 22.0 +/- 0.9 microgram/ml; n = 14) or 381-415 days (23.0 +/- 2.5 to 23.1 +/- 2.5 micrograms/ml; n = 5) of medroxyprogesterone treatment. Similarly, the mean pretreatment plasma T4 concentration was unaltered by acute (9.7 +/- 0.6 to 9.7 +/- 0.4 microgram/dl; n = 14) or chronic (11.1 +/- 1.2 to 11.4 +/- 1.0 microgram/dl; n = 5) medroxyprogesterone therapy. We conclude that progestational agents alone do not modify circulating TBG or total T4 concentrations in men.

Plasma atriopeptin concentrations in hyperthyroidism, euthyroidism, and hypothyroidism: studies in man and rat.

Atriopeptin (AP) is a polypeptide produced by atrial myocytes that is capable of inducing diuresis, natriuresis, and vasodilatation. Because thyroid dysfunction is known to be associated with alterations in both renal function and vasomotor control, we investigate the possible effects of varying thyroid function on AP in humans and rats. Plasma AP concentrations were determined in hyperthyroid and hypothyroid patients and normal subjects. Plasma AP was also measured in some patients after the iv infusion of 1 L 150 mmol/L NaCl and after treatment of hyperthyroidism or hypothyroidism. Plasma and atrial AP concentrations were measured in hyperthyroid, euthyroid, and hypothyroid rats. Plasma AP concentrations did not differ in the hyperthyroid (n = 22), euthyroid (n = 45), and hypothyroid (n = 16) subjects [47.1 +/- 18.2 (mean +/- SD), 45.1 +/- 28.9, and 42.4 +/- 20.0 pg/mL, respectively]. After NaCl infusion, mean plasma AP concentrations did not increase significantly in any of the three groups. Treatment of hyperthyroidism and hypothyroidism did not result in a significant change in plasma AP levels. In contrast, plasma AP concentrations were significantly higher in T4-treated (hyperthyroid) rats than in either euthyroid or propylthiouracil-treated (hypothyroid) rats [621 +/- 17 vs. 266 +/- 41 (P less than 0.01) and 210 +/- 28 pg/mL (P less than 0.001), respectively], whereas atrial AP contents were similar in the three groups of rats. We conclude that hyperthyroidism and hypothyroidism in man are not associated with significantly altered plasma AP concentrations. The higher plasma AP levels in T4-treated rats may reflect the relatively shorter duration or greater severity of thyroid dysfunction or thyroid hormone-induced myocardial hypertrophy in the animals.

Elevated plasma adrenocorticotropin concentration as evidence of limited adrenocortical reserve in patients with adrenomyeloneuropathy.

Adrenal insufficiency occurs in approximately two thirds of patients with adrenomyeloneuropathy. Its development may precede or follow the onset of neurological disease. To define the sensitivity of various tests of adrenal cortical function, we reviewed adrenocortical function tests in 28 patients with adrenomyeloneuropathy who had normal ACTH stimulation tests at the time of enrollment into an ongoing dietary study. Endocrine studies performed at 6-month intervals included a conventional ACTH stimulation test, plasma ACTH and cortisol concentrations, and 24-h urinary cortisol and aldosterone excretion rates. Eleven patients (39%) developed an elevated plasma ACTH concentration after a median follow-up of 3 yr. Their 24-h urinary cortisol and plasma basal and ACTH-stimulated cortisol concentrations were all normal. The mean basal cortisol level tended to be lower in patients who had increased plasma ACTH levels than in patients who maintained a normal plasma ACTH concentration during the study period (408 +/- 22 vs. 491 +/- 33 nmol/L; P = 0.05). Patients who had an increased plasma ACTH concentration and symptoms consistent with adrenal insufficiency had a lower mean 24-h urinary free cortisol level than those with normal plasma ACTH (196 +/- 22 vs. 281 +/- 30 nmol/day; P < 0.05). Plasma ACTH concentrations were persistently elevated in six patients in whom subsequent values were available. One individual later developed a subnormal ACTH-stimulated cortisol concentration consistent with overt adrenal insufficiency. Our results suggest that conventional provocative and integrative tests of adrenocortical function may not be sufficient to identify patients with adrenomyeloneuropathy who have compensated adrenal hypofunction. An elevated plasma ACTH concentration may represent an early marker for adrenocortical dysfunction and incipient adrenal insufficiency in AMN patients.

Rapid pituitary and peripheral tissue responses to intravenous L-triiodothyronine in hypothyroidism.

Acute cardiovascular, renal, pulmonary, metabolic, and pituitary responses to therapy of hypothyroidism with 25 micrograms iv T3 (group I G-I, n = 11) or 50 micrograms iv T3 (group II, G-II, n = 10)/day for 1 week have been studied. Serum T3 levels were acutely normalized in both groups with the mean basal serum T3 levels (X +/- SE) after 7 days, 98 +/- 10 micrograms/dl and 229 +/- 19 ng/dl, respectively. Myocardial performance, noninvasively assessed by the pulse wave arrival time (QKd) and the phonocardiographic systolic time interval ratio was significantly altered after 1 day of therapy (QKd for G-I = -10 +/- 4 msec, P less than 0.05; and for G-II = -18 +/- 14 msec, P less than 0.01). After 7 treatment days, both the mean QKd (203 +/- 7 msec, P less than 0.001) and phonocardiographic systolic time interval ratio (0.41 +/- 0.02, P less than 0.01) were within the normal range in G-II. Abnormal pretreatment renal excretion of an oral water load (G-I, 65 +/- 6%; and G-II, 57 +/- 6%) was also reversed after 1 week (G-I, 84 +/- 5%, P less than 0.05; and G-II, 89 +/- 5%, P less than 0.01). Patients with blunted hypercapnic (n = 6) and hypoxic (n = 4) ventilatory drives were improved in both groups after 6 days. The mean basal metabolic rate, serum cholesterol, and serum creatine phosphokinase were altered by the week of therapy in a dose-response manner, and were in the normal range in G-II. Pituitary TSH secretion was promptly suppressed in both groups. Two hours after the first T3 dose, the mean serum TSH for G-I and G-II decreased to 85% (P less than 0.02) and 70% (P less than 0.001) of their respective pretreatment values. After 7 days of therapy, the mean basal TSH levels had declined to 75% (P less than 0.001) and 5% (P less than 0.001%) of pretreatment, respectively. In comparison with previous observations of responses to 100 micrograms/day iv T4 for 1 week, the 25 micrograms dose T3 was equivalent in terms of changes in basal serum T3 and peripheral (nonpituitary) tissue responses, but less effective than T4 in lowering serum TSH. Based on these parameters, 50 micrograms/day iv T3 was the most effective of the three regimens within this time frame. The implications of these observations in the clinical management of severe complicated myxedema are discussed.

Molecular diagnosis of residual and recurrent thyroid cancer by amplification of thyroglobulin messenger ribonucleic acid in peripheral blood.

Serum thyroglobulin measurement by immunoassay is used to detect residual or recurrent thyroid cancer after thyroid ablation. However, the usefulness of immunoassay is limited by both the requirement for thyroid hormone withdrawal to attain optimal test sensitivity and interference by antithyroglobulin antibodies. To circumvent these problems, we amplified thyroglobulin messenger ribonucleic acid (mRNA) in peripheral blood using RT-PCR and compared the accuracy of this test to serum thyroglobulin immunoassay in patients with thyroid cancer. Thyroglobulin mRNA was amplified from peripheral blood of 77 patients who had undergone thyroidectomy for well differentiated thyroid cancer, 68 of whom while taking thyroid hormone for TSH suppression. Patient staging was based on the most recent radioiodine scan after thyroid hormone withdrawal. Ten normal control subjects were also studied. Among patients taking T4, thyroglobulin mRNA was detected in 26 of 33 patients with either thyroid bed or metastatic iodine-avid tissue on most recent withdrawal scan (79%), whereas serum thyroglobulin was detected in 12 of these 33 patients (36%; P < 0.001). Thyroglobulin mRNA was detected in 7 of 35 patients (20%) with negative radioiodine scans, 12 of 19 patients (63%) with radioiodine uptake in the thyroid bed, and all 14 patients with metastases, including 2 patients with antithyroglobulin antibodies. Thyroglobulin mRNA was detected in all 10 normal subjects. Epithelioid cells that stained strongly with antithyroglobulin antibodies were identified in blood. Detection of circulating thyroglobulin mRNA is a more sensitive marker of residual thyroid tissue or cancer than immunoassay for serum thyroglobulin, particularly in patients treated with thyroid hormone or who have circulating antithyroglobulin antibodies.