Intrasellar plasmacytoma presenting as a non-functional invasive pituitary macro-adenoma: case report & literature review.

We report an uncommon case of an intrasellar plasmacytoma presenting as a non-functional invasive pituitary macro-adenoma as the first manifestation of multiple myeloma. A 57 year old woman was referred to our department with a presumed diagnosis of a non-functioning pituitary macro-adenoma. She reported a 3 month history of headaches and a 2 week history of sudden onset of right facial numbness. Preoperative endocrine evaluation was remarkable only for a modestly elevated serum prolactin. A magnetic resonance imaging (MRI) scan revealed 3.6 x 5 x 4 cm enhancing homogeneous intrasellar mass with extension into the sphenoid and cavernous sinuses bilaterally; the optic chiasm was not displaced. She underwent transphenoidal surgery of the sellar lesion. The surgical specimen was heavily infiltrated with abnormal plasma cells, which stained almost exclusively for Kappa light chain immunoglobulins. An extensive investigation was undertaken to look for occult myelomatous disease. A diagnosis of multiple myeloma was made 1 month later based on a combination of clinical, pathological and radiologic features. She underwent radiation therapy directed towards the residual sellar tumor, followed by chemotherapy and autologous stem cell transplantation. Review of the world literature revealed only 22 previous reports of patients in whom a solitary plasmacytoma or multiple myeloma first presented as a sellar mass; in all cases mimicking clinically and radiologically a non-functioning invasive pituitary adenoma however with additional cranial nerve involvement. Intrasellar plasma cell tumors are rare tumors which may mimic non-functioning invasive pituitary tumors. The diagnosis should be suspected in patients with well preserved anterior pituitary function and cranial nerve neuropathies in the presence of significant sellar destruction.

Parathyroid adenoma after radioactive iodine therapy for multinodular goiter.

The development of hyperparathyroidism after radioactive iodine (RAI) therapy has been reported in 38 cases in the literature. However, the development of a parathyroid adenoma after RAI therapy for a hyperfunctioning multinodular goiter has not been reported. This report describes the pathologic and operative finding on a patient with both hyperthyroidism and hyperparathyroidism, which was diagnosed after previous RAI therapy for a toxic, multinodular goiter.

The use of oral radiographic contrast agents in the management of hyperthyroidism.

Oral iodinated radiographic contrast agents such as ipodate and iopanoic acid form an important part of the armamentarium used to treat hyperthyroidism. They rapidly and dramatically reduce serum triiodothyronine (T3) levels by inhibiting conversion of thyroxine (T4) to T3 in the periphery and by blocking secretion from the thyroid. Potential risks from the large iodine load resulting from their use limit their widespread applicability. In addition, they are ineffective when used alone on a long-term basis. However, these agents may be especially useful in treating thyrotoxic patients preoperatively, in neonatal Graves' disease, in massive levothyroxine ingestion, and when other conventional antithyroid drugs are unsuccessful or contraindicated.

Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors?

Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone, is linked to mutations in the thyroid hormone receptor-beta (TR beta) gene. The purpose of this study was to determine whether the clinical phenotypes of RTH can be translated in terms of functional impairment of the corresponding mutant TR beta. Data from 124 subjects with RTH representing 18 different mutant TR beta s, showed that serum free T4 levels correlated with the degree of T3-binding impairment of the corresponding TR beta in 12 of these mutant TR beta s (group I), but not in the remaining 6 (group II). In subjects from both groups studied in detail by the administration of incremental doses of T3, the degree of thyrotroph resistance to T3 correlated with the magnitude of endogenous free T4 elevation at baseline, but did not parallel the resistance of peripheral tissues. In transfection studies, all group I mutant TR beta s inhibited positive transactivation by the wild type TR beta s to a similar degree in the presence of 1 nmol/L T3, whereas group II mutant TR beta s exerted a weaker inhibition that was not related to their T3-dependent trans-activation when tested alone. Similar results were obtained with negatively regulated reporter genes. It is concluded that the clinical severity of RTH, determined by thyrotroph resistance, can be predicted from the degree of T3 binding impairment and dominant negative potency of mutant TR beta s, but the degree of peripheral tissue resistance and related clinical manifestations is limited by putative genetic or environmental factors that modulate the effect of thyroid hormone.

Serum thyrotropin and prolactin in the syndrome of generalized resistance to thyroid hormone: responses to thyrotropin-releasing hormone stimulation and short term triiodothyronine suppression.

Serum TSH and PRL levels and their response to TRH were measured in 11 patients with generalized resistance to thyroid hormone (GRTH), 6 euthyroid subjects, and 6 patients with primary hypothyroidism. TSH and PRL levels and their response to TRH were also measured after the consecutive administration of 50, 100, and 200 micrograms T3 daily, each for a period of 3 days. Using a sensitive TSH assay, all GRTH patients had TSH values that were elevated or within the normal range. On the basis of a normal or elevated TSH level, GRTH patients were classified as GRTH-N1 TSH (5 patients) or GRTH-Hi TSH (6 patients), respectively. Only GRTH patients with previous thyroid ablative therapy had basal TSH values greater than 20 mU/L. TSH responses, in terms of percent increment above baseline, were appropriate for the basal TSH level in all subjects. No GRTH patient had an elevated basal PRL level. PRL responses to TRH were significantly increased only in the hypothyroid controls compared to values in all other groups. On 50 micrograms T3, 7 of 12 (58%) nonresistant (euthyroid and hypothyroid) and 1 of 11 (9%) resistant subjects had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, 2 of 12 (17%) nonresistant and 4 of 11 (36%) resistant subjects had a greater than 50% suppression of the PRL response to TRH. On 200 micrograms T3, all subjects, except for 1 with GRTH, had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, while 11 of 12 (92%) nonresistant subjects had a greater than 50% reduction of the PRL response to TRH, only 3 of 10 (30%) resistant patients showed this degree of suppression (P less than 0.005). Without previous ablative therapy, serum TSH in patients with GRTH is usually normal or mildly elevated. The TSH response to TRH is proportional to the basal TSH level and is suppressed by exogenous T3. However, on 200 micrograms T3 basal TSH was not detectable (less than 0.1 mU/L) in all euthyroid subjects, but it was measurable in three of four GRTH patients with normal TSH levels before T3 treatment. PRL levels in GRTH are normal even when TSH is elevated. The PRL response to TRH is not increased in GRTH. In all subjects, exogenous T3 suppresses the PRL response to TRH to a lesser degree than the TSH response, but this difference is much greater in patients with GRTH.

Limitations to the use of a sensitive assay for serum thyrotropin in the assessment of thyroid status.

In the majority of clinical settings, a suppressed serum thyrotropin (s-TSH) level determined by the new sensitive assays is diagnostic of thyrotoxicosis. This has led to its proposed use as a screen for thyroid disease. However, s-TSH may be suppressed in conditions other than thyrotoxicosis. We retrospectively reviewed s-TSH measurements made in a large heterogeneous population to determine in which settings a suppressed value could potentially lead to misdiagnosis. We found that a suppressed s-TSH level was useful in making the diagnosis of autonomous thyroid function and in the assessment of thyroid hormone replacement therapy in patients with primary, but not central, hypothyroidism. Hyperthyroidism caused by either intrinsic thyroid disease or thyroid hormone administration accounted for 83% (111/134) of suppressed values; however, central hypothyroidism, nonthyroidal illness, acute psychiatric illness, or the administration of medication was responsible for this finding in 17% (23/134). While a suppressed s-TSH level is generally excellent in the diagnosis of pituitary suppression by thyroid hormone, in specific clinical settings, a suppressed s-TSH level may be seen in the absence of thyroid hormone excess. The limitations of its use as a first-line screen in those conditions must be recognized.

A new inherited abnormality of thyroxine-binding globulin (TBG-San Diego) with decreased affinity for thyroxine and triiodothyronine.

Evaluation of a family in which males were clinically euthyroid despite having low serum total T4 (TT4) and free T4 index (FT4I) values revealed the presence of a new inherited T4-binding globulin (TBG) variant (TBG-San Diego). Two brothers had low TT4 (39 and 49 nmol/L; normal range, 64-154 nmol/L) and FT4I (4.0 and 4.4; normal range, 6.0-10.5) values, while their grandfather, despite treatment with T4, had a low TT4 (53 nmol/L) and normal FT4I (7.2) in the presence of suppressed TSH (less than 0.1 mU/L). When measured by RIA, the mean TBG concentration (TBG-RIA) of the three affected males was low normal [160 +/- 56 (+/- SD) nmol/L; normal range, 151-253]. Their TBG-binding capacity measured by a T4 binding assay at saturation (TBG-CAP) was similar, giving a mean TBG-RIA/TBG-CAP ratio not significantly different from 1.0. In these males, the TBG affinity for T4 (Ka = 0.48 +/- 0.04 x 10(10) mol-1) was less than that in subjects with the common type TBG (TBG-C; Ka = 1.10 +/- 0.14 x 10(10) mol-1; P less than 0.0001) and similar to that in Aboriginal males from Australia with the variant TBG-A (0.52 +/- 0.10 x 10(10) mol-1). TBG affinity for T3 in the affected males (Ka = 0.68 +/- 0.05 x 10(9) mol-1) was less than that in subjects with TBG-C (1.39 +/- 0.12 x 10(9) mol-1; P less than 0.00001), but greater than that in males with TBG-A (0.44 +/- 0.03 x 10(9) mol-1; P less than 0.0005). The rate of TBG denaturation at 56 C was increased in the affected males (t1/2 = 28.4 and 26.9 min) compared to that in subjects with TBG-C (t1/2 = 54.1 +/- 7.1 min), but was lower than that in males with TBG-A (t1/2 = 20.8 +/- 1.9). A value intermediate between those in affected males and normal subjects was found in serum from an obligatory heterozygote. Microheterogeneity on isoelectric focusing was normal. The exact nature of this structural TBG variant is not yet known. The presence of a TBG mutant should be considered in healthy, clinically euthyroid patients with low serum TT4 and free T4 index values, especially when such low values are found in several members of the same family.

Normal cellular uptake of thyroxine from serum of patients with familial dysalbuminemic hyperthyroxinemia or elevated thyroxine-binding globulin.

To determine whether thyroid hormone-binding proteins in serum, particularly albumin, facilitate the transfer of T4 into human tissues, we studied cellular T4 uptake (CT4) by human liver (Hep G2) cells from medium containing serum from subjects with familial dysalbuminemic hyperthyroxinemia (FDH) and acquired and familial T4-binding globulin (TBG) excess and patients with normal T4-binding to albumin and normal TBG concentrations. Serum from nine subjects with FDH whose mean serum total T4 (TT4) concentration was 203 +/- 27 nmol/L were matched for TT4 concentrations with serum from nine subjects with acquired TBG excess (TT4, 201 +/- 23 nmol/L) and nine subjects with thyrotoxicosis and normal TBG concentrations (TT4, 205 +/- 28 nmol/L). The subjects' CT4 results were compared to their serum free T4 concentration, measured by equilibrium dialysis (DT4), and their serum free T4 index (FT4I) value. The mean serum DT4 value for the subjects with FDH (23 +/- 5 fmol/L) and those with TBG excess (23 +/- 3 fmol/L) were normal, whereas it was elevated (44 +/- 9 fmol/L; P less than 0.001) for the thyrotoxic patients with normal TBG concentrations. The mean CT4 value also was normal for the subjects with FDH (37.7 +/- 4.9 fmol/plate) and those with TBG excess (36.6 +/- 4.6 fmol/plate), but was elevated for the thyrotoxic patients (62.3 +/- 11.2 fmol/plate; P less than 0.001). In all three groups studied, the relationship between individual CT4 and DT4 values was similar to that previously found in subjects with no T4-binding protein abnormalities. The mean serum FT4I value was lower for the subjects with acquired TBG excess (111 +/- 22) than for the subjects with FDH (133 +/- 22; P less than 0.05), and it was much higher for the subjects with thyrotoxicosis (221 +/- 31; P less than 0.001). In the subjects with FDH and those with thyrotoxicosis the normal relationship between CT4 and FT4I was maintained, while in the subjects with acquired TBG excess, FT4I values were lower than expected. In seven of the nine subjects with TBG excess, the abnormality was associated with conditions known to increase its sialic acid content: hepatitis (one subject), pregnancy (four subjects), and estrogen therapy (two subjects). The CT4 values were similar in nine subjects with acquired TBG excess (seven pregnant women and two subjects with chronic active hepatitis) and five subjects with familial TBG excess (34.8 +/- 4.3 vs. 34.0 +/- 8.6 fmol/plate, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of estrogen on the synthesis and secretion of thyroxine-binding globulin by a human hepatoma cell line, Hep G2.

Hyperestrogenemia in humans increases both the concentration of serum T4-binding globulin (TBG) by 2- to 3-fold and the proportion having anodal mobility on isoelectric focusing (IEF). As TBG is synthesized in the liver, we studied the effect of estrogen on TBG synthesis, secretion, and degradation by cultured human hepatocarcinoma cells (Hep G2). beta-Estradiol in concentrations in the range found in pregnancy (10(-7) M) had no effect on the accumulation of immunoreactive TBG in medium over 4 days. The absence of fetal calf serum or phenol red did not alter these findings. The amount of [35S]TBG accumulated 6 h after addition of [35S]methionine was not influenced by exposure to estrogen or to serum obtained from pregnant women. However, 10(-5) M beta-estradiol suppressed TBG more severely than albumin synthesis (34% vs. 9%). The lack of an estrogen effect on TBG synthesis and secretion was supported by experiments showing no effect of estrogen on the disappearance of TBG added to the medium or the accumulation of cytoplasmic TBG mRNA. The same cultures responded to estrogen by a 10-fold increase in nuclear estrogen receptor binding sites and a 2-fold increase in apolipoprotein CII. As TBG in serum, the rate of heat denaturation was not altered in TBG synthesized by Hep G2 cells in the presence of estrogen. In contrast to the effect on TBG in serum, in Hep G2 cells estrogen did not produce an anodal shift on IEF, or increased its proportion not bound to Concanavalin A, nor reduced its clearance rate when injected into rats. However, even untreated Hep G2 cells synthesized TBG with a larger number of anodal IEF bands and proportion of Concanavalin A excluded material than TBG in pregnancy serum. Results support our hypothesis, based on analysis of TBG in pregnancy, that estrogen-induced serum TBG elevation may not be mediated through an increase in synthesis. The failure to observe estrogen induced changes in oligosaccharide structure does not exclude estrogen responsivity of Hep G2 cells. Such effect could be masked by the marked constitutive increase in number of oligosaccharide chain antennae typical in this and other neoplastic tissues.

Sex hormone-binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes after short term triiodothyronine administration.

Thyroid hormone is one of several factors that modulate the level of sex hormone-binding globulin (SHBG) in serum. SHBG levels are usually elevated in thyrotoxicosis and have been reported to be normal in a few patients with generalized resistance to thyroid hormone (GRTH). This study was designed to determine whether basal serum SHBG levels or the SHBG response to short term T3 administration could be used as an index of thyroid hormone action and thus serve as a test for the evaluation of patients suspected of having peripheral tissue resistance to thyroid hormone. Serum SHBG, total T4, free T4 index (FT4I), total T3, and TSH levels were measured in 21 normal subjects, 28 hypothyroid patients, 20 thyrotoxic patients, and 10 patients with GRTH. Excluding patients with GRTH, serum basal SHBG values were correlated with FT4I values (r = 0.66; P less than 0.0001). Mean SHBG levels in the patients with GRTH [37.6 +/- 16.2 (+/- SD) nmol/L] were not significantly different from those in the normal subjects (35.1 +/- 19.3 nmol/L) or hypothyroid patients (26.3 +/- 17.1 nmol/L), but were significantly lower than those in the thyrotoxic group (64.7 +/- 19.2 nmol/L; P less than 0.001). All 10 patients with GRTH had basal SHBG values in the normal range, but 7 of 20 (35%) thyrotoxic patients also had normal basal SHBG values. T3 was given orally for three sequential 3-day periods at doses of 50, 100, and 200 micrograms daily to 7 normal subjects, 11 hypothyroid and 3 thyrotoxic patients, and all 10 patients with GRTH. The serum SHBG concentration was measured on the last day at each dosage level. During T3 administration, SHBG levels increased in all individuals with normal tissue responsiveness. The increase above the basal value (delta SHBG) at each T3 dose was similar in normal, hypothyroid, and thyrotoxic individuals (non-resistant subjects). After administration of 50 micrograms T3 daily, the mean delta SHBG level was decreased [-2.9 +/- 5.3 (+/- SD) nmol/L] in the resistant patients and increased (4.0 +/- 4.9 nmol/L; P less than 0.005) in the nonresistant subjects. After administration of 100 micrograms T3 daily, the mean delta SHBG was -4.5 +/- 6.8 nmol/L in the resistant patients and 8.6 +/- 5.1 nmol/L (P less than 0.0001) in the nonresistant subjects. Serum SHBG decreased by more than 2 nmol/L in 6 of 10 (60%) resistant patients, but in no nonresistant subject.(ABSTRACT TRUNCATED AT 400 WORDS)

Myocardial mechanics in hyperthyroidism: importance of left ventricular loading conditions, heart rate and contractile state.

Hyperthyroidism has been reported to affect all of the major determinants of left ventricular performance in a manner that would augment ventricular shortening characteristics. The hypothesis tested in this study is that reduced afterload in conjunction with increased preload and heart rate, rather than augmented contractility, accounts for much of the increase in left ventricular performance noted previously in these patients. To investigate this hypothesis, 11 hyperthyroid patients were evaluated serially over 4 +/- 2 months. With therapy, serum total thyroxin (T4) decreased significantly (p less than 0.001). Ventricular hemodynamics were assessed by two-dimensional targeted M-mode echocardiograms and calibrated carotid pulse tracings. Ventricular preload was estimated by end-diastolic dimension, whereas afterload was measured as end-systolic wall stress. Overall left ventricular performance was quantitated by the extent and velocity of shortening, whereas myocardial work was assessed by ventricular systolic stress-length relations. With therapy, overall left ventricular performance declined (p less than 0.01). This change was associated with no change in end-diastolic dimension or end-systolic wall stress, and a 24% fall in heart rate (p less than 0.01). This latter finding has been shown previously to have no significant effect on left ventricular contractile state over the range of heart rates encountered in this study. In all cases, the end-systolic stress/rate-corrected shortening velocity relation fell with attainment of normal thyroid status, characteristic of a decline in contractility. There was a strong positive correlation between left ventricular contractility and serum thyroid hormone level (r = 0.83). In addition, ventricular minute work declined with therapy (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of thyroxine uptake from serum by cultured human hepatocytes as an index of thyroid status: reduced thyroxine uptake from serum of patients with nonthyroidal illness.

The uptake of T4 from human serum by cultured human hepatoma cells, Hep G2, was compared with the free T4 estimates by equilibrium dialysis (DT4) and a resin uptake method (FT4I). The cellular uptake of T4 (CT4) was highly correlated with DT4 values (r = 0.97; P less than 0.0005) and FT4I values (r = 0.99; P less than 0.0005) in sera from euthyroid subjects and hypothyroid and thyrotoxic patients. In patients with abnormal levels of serum T4-binding globulin, the fractional uptake of T4 decreased as the TBG level increased, and the CT4 value remained within the normal range. Addition of increasing amounts of T4 to serum from a hypothyroid patient did not alter the relationships between CT4 and FT4I and between CT4 and DT4. DT4 and CT4 measurements were compared in sera from 13 patients with severe nonthyroidal illness (NTI). Six samples had DT4 values that clearly overestimated the cellular uptake, 2 patients had DT4 values in the thyrotoxic range but normal CT4 values, and 2 patients had DT4 values in the midnormal range and CT4 values below normal. When FT4I and CT4 values were compared in 19 NTI patients, 5 had FT4I values below the normal range and normal CT4 values. Overall, among patients with NTI, FT4I was low in 11 (58%), normal in 8 (42%), and high in 0; CT4 was low in 6 (32%), normal in 13 (68%), and high in 0, and DT4 was low in 2 (15%), normal in 9 (69%), and high in 2 (15%). In patients with NTI, the results of in vitro estimations of free T4 do not always correlate with the transfer of T4 to tissues, as assessed by T4 uptake in human hepatoma cells. In patients with NTI, equilibrium dialysis may overestimate and resin uptake measurements may underestimate the amount of T4 taken up by tissues. In some patients with severe NTI, tissue uptake of T4 is reduced.

Variant thyroxine-binding globulin in serum of Australian aborigines: its physical, chemical and biological properties.

Low serum total thyroxine (TT4) and triiodothyronine (TT3) is found in approximately 40% of Australian Aborigines. Studies were carried out to characterize the properties of thyroxine-binding globulin (TBG) in these Australian Aborigines to explain the observed reduction of thyroid hormone concentration in their serum. TBG from Aborigines with low serum TT4 concentrations was compared to TBG from Aborigines with normal TT4 concentration and Caucasians and American Blacks with normal or reduced serum TBG levels due to familial partial TBG deficiency. TBG from Aborigines with low serum TT4 concentrations had a reduced affinity for thyroid hormone (Ka). The Ka for T4 was 54% and for T3 30% of the Ka values for TBG from Aborigines with normal TT4 concentration or non-Aborigines. Maximal binding values were in agreement with TBG measurements by RIA for Aborigines with low or normal serum TT4 and for non-Aborigines. An increase in the rate of heat denaturation of TBG at temperatures from 54 to 60 C was also observed in sera from Aborigines with low TT4. The heat lability was lowered by 2 C. The low concentration of TT4 in serum of these Aborigines could not explain this higher heat lability of TBG since only addition of greater than 80-fold the physiologic T4 concentration obliterated the difference of heat inactivation by denaturation.(ABSTRACT TRUNCATED AT 250 WORDS)

Variant thyroxine-binding globulin in serum of Australian aborigines: a comparison with familial TBG deficiency in Caucasians and American blacks.

About 40% of clinically euthyroid Australian Aborigines have low concentrations of total thyroxine (TT4) and triiodothyronine (TT3) in serum. While the finding of normal concentrations of serum thyrotropin (TSH) in such individuals is compatible with their eumetabolic state, the reason for the finding of a low free T4 index (FT4I) has been unclear. A genetic variant of T4-binding globulin (TBG) with reduced affinity for T4 has been suggested but decrease in the absolute concentration of TBG has also been reported. In this study, we measured various parameters of thyroid function in 20 serum samples from euthyroid Australian Aborigines selected for their low TT4 levels. Results were compared to those obtained in serum samples from Caucasians and American Blacks with inherited partial TBG deficiency, 15 of which were matched to the Aborigines by their TBG and 20 by their TT4 concentrations. Results were also compared with those from another group of 20 samples from Caucasians and American Blacks with normal TBG concentration, matched to the Aborigines by their serum TT4 concentration. TBG in serum from these Australian Aborigines was immunologically identical to that in Caucasians and American Blacks in terms of parallelism of serially diluted samples in the TBG radioimmunoassay (RIA).(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of thyroxine-binding globulin secreted by a human hepatoma cell line.

T4-binding globulin (TBG) is a glycoprotein synthesized by the liver and is the principal carrier of T4 and T3 in serum. In this report, we demonstrate that the Hep G2 cell line, derived from a human hepatoblastoma, synthesizes and secretes TBG, the properties of which were characterized. Hep G2 cells secreted TBG into the medium after more than 100 transfers in tissue culture conditions. At confluency and after changing to serum-free culture conditions, TBG accumulation into the medium was linear for 3 days and constituted approximately 0.16% of the proteins synthesized over 24 h. Its abundance relative to albumin is 10-fold greater than that found in normal human serum. TBG secreted by the Hep G2 cells was indistinguishable from native normal human serum TBG, as determined immunologically, by electrophoresis on polyacrylamide gel in denaturing and nondenaturing conditions, and by isoelectric focusing. It also specifically bound T4 and T3, albeit with slightly reduced affinity, and had increased heat lability. Although slightly different from normal serum TBG in caucasians, the physical and biological properties of the Hep G2-derived TBG are similar to those of the variant TBG found in the serum of some healthy Australian Aborigines.