Radioiodine uptake and thyroid scintiscanning.

This article reviews the technical aspects and clinical applications of the radioactive iodine uptake test and thyroid scintiscanning. The choice of radionuclide for the tests is discussed. The main uses of the radioactive iodine uptake test are to identify the cause of hyperthyroidism and to aid in the selection of the I-131 dose in the treatment of hyperthyroidism. Factors other than thyroid diseases that alter uptake results are identified. Thyroid scintiscanning is used in the identification of normal and ectopic thyroid tissue, in the diagnosis of the cause of a patient's hyperthyroidism, and as part of the evaluation of selected patients with thyroid nodules.

A clear cell variant of follicular carcinoma presenting as an autonomously functioning thyroid nodule.

We report a case of an autonomously functioning thyroid nodule (AFTN) that proved to be almost exclusively a clear cell variant of follicular carcinoma. AFTNs are generally felt to be benign lesions with exceptions forming the basis of case reports. Likewise, clear cell tumors of the thyroid are rare. To our knowledge, this combination of two unusual thyroid conditions has not been previously reported. The initial scans of this patient were so characteristic for a degenerating AFTN that attention was first directed toward a very large contralateral lobe. While it is debatable whether all AFTNs should be biopsied, on the basis of this and other cases, it is recommended that AFTNs that contain a central photopenic area on scan be biopsied to be sure that cystic degeneration, a commonly seen phenomenon in larger AFTNs, is indeed present rather than a malignancy.

Glucose utilization in muscle fiber types: use of the partial pancreatectomized rat model to distinguish effects of glucose and insulin on insulin resistance.

We have used the partially pancreatectomized infusion model in order to examine individual and combined effects of glucose and insulin on insulin resistance in rat skeletal muscles. Infusing glucose or insulin can produce animals which are hyperglycemic, hyperinsulinemic, or both. Individual and combined effects of chronic hyperglycemia and hyperinsulinemia on basal and insulin-mediated glucose utilization indices in glycolytic and oxidative muscle fibers were examined by 2-deoxyglucose uptake. Hyperglycemia reduced the basal glucose utilization index by 49% and hyperinsulinemia by 55%, while combined hyperglycemia + hyperinsulinemia diminished 2-deoxyglucose uptake by 69%. Maximally insulin-stimulated utilization was diminished only 28% under hyperglycemia but by 81% in the hyperinsulinemic state. In order to assess utilization in individual muscle fibers, uptake was examined in three tissues of differing fiber composition. The slow-twitch oxidative soleus muscle demonstrated greater basal uptake than the fast-twitch gastrocnemius (glycolytic) and quadriceps (oxidative) muscles. In addition basal (though not maximally insulin-stimulated) glucose utilization in the fast-twitch fibers was affected by chronic glucose and insulin to a greater extent than the slow-twitch soleus muscle, indicating that chronic hyperglycemia is more likely to precipitate insulin resistance in fast-twitch muscles. Significant differences in glucose metabolism among muscle fiber types suggests that results from insulin resistance studies in mixed muscles may be skewed according to their fiber composition.

Mechanisms of insulin-resistant glucose utilization in rat skeletal muscle.

Defects in glucose uptake are among the primary defects associated with peripheral insulin resistance, but fundamental mechanisms leading to this state are poorly understood. In order to elucidate mechanisms leading toward defects in glucose transport, we have used a partially pancreatectomized infusion (PxI) animal model with infusions of saline, glucose, or insulin to examine individual and combined effects of hyperglycemia and hyperinsulinemia on skeletal muscle glucose utilization. Moderate hyperglycemia induced by pancreatectomy reduced basal hindlimb muscle glucose utilization by 57% without affecting maximal insulin-stimulated glucose utilization; insulin administered in an amount sufficient to correct this hyperglycemia did not alter basal glucose utilization, but maximal insulin-stimulated glucose utilization was sharply diminished (75%); hyperglycemia with hyperinsulinemia similarly reduced basal and maximal insulin-stimulated glucose utilization. In order to establish the role of the glucose transporter protein in these insulin-resistant states, we quantified GLUT 4 content by immunoblotting and GLUT 4 mRNA by solution hybridization/RNAse protection assays. Hyperglycemia (2 weeks) reduced total muscle GLUT 4 protein content (53%) and mRNA (46%), while subsequent hyperinsulinemia (72 h) with either normo- or hyperglycemia partially restored both total GLUT 4 protein and mRNA levels. As insulin-stimulated GLUT 4 content in plasma membranes was not diminished by combined hyperglycemia/hyperinsulinemia, these results indicate functional GLUT 4 translocation in this model and suggest suppression of GLUT 4 transporter activity.

Treatment of hyperthyroidism with radioactive iodine.

Treatment of hyperthyroidism with RAI has been performed for more than a half century with efficacy and safety. For its optimal use, the physician must employ appropriate patient selection criteria and clinical judgment concerning pretreatment patient preparation. The dose of the 131I needed remains an area of uncertainty and debate; thus far, it has not been possible to resolve the trade-off between efficient definitive cure of hyperthyroidism and the high incidence of post-therapy hypothyroidism. Early side effects are uncommon and readily manageable. Other than the need for long-term monitoring and, in most cases, lifelong L-T4 treatment, late adverse consequences of this treatment remain only conjectural. The available follow-up studies support the current majority opinion of North American thyroid specialists that RAI treatment is an excellent choice for most hyperthyroid patients.

Graves' disease triggered by autoinfarction of an autonomously functioning thyroid adenoma.

A patient whose nontoxic autonomously functioning thyroid adenoma had been stable for at least 3 yr developed enlargement of the nodule and hyperthyroidism. It was assumed the hyperthyroidism was caused by evolving toxicity in the autonomous adenoma, but imaging showed the nodule had undergone infarction and the hyperthyroidism was secondary to Graves' disease. This case demonstrates the necessity of thyroid imaging in patients with nontoxic autonomously functioning thyroid adenomas when there is a change in nodule size or thyroid function which requires treatment.

Differential diagnosis of a tender goiter.

Subacute thyroiditis is generally felt to have a viral etiology, and the diagnosis is usually obvious when the patient presents with a diffusely enlarged and very tender thyroid gland associated with elevated free T4 levels, elevated sedimentation rate, low radioiodine uptake and/or nonvisualization on scan and often some systemic symptoms. Subacute thyroiditis can be unilateral or focal (1,2). Corticosteroids are very effective in relieving symptoms of subacute thyroiditis, often within 24 hr (3). Three patients are presented where the initial impression was subacute thyroiditis, there was a clinical response to prednisone, but none of the patients actually had subacute thyroiditis.

Regulation of basic fibroblast growth factor expression by transforming growth factor beta in cultured human prostate stromal cells.

Basic fibroblast growth factor (bFGF) and transforming growth factor beta 1 (TGFbeta1) are potential autocrine growth regulators of the prostatic stroma, and therefore may play a role in the development of benign prostatic hyperplasia (BPH). We reported that TGFbeta1 increased bFGF and bFGF mRNA expression in cultured human prostate stromal cells (PS). The current study extends those studies and investigates the mechanism by which TGFbeta1 upregulates the level of bFGF mRNA. A solution hybridization assay was used to quantitate bFGF mRNA. Treatment of PS for 6 hr with TGFbeta1 (1 ng/ml) maximally stimulated bFGF mRNA expression. TGFbeta2 and TGFbeta3 were similarly active in upregulating bFGF mRNA. TGFbeta1 or cycloheximide each increased bFGF mRNA about 3-fold. The effect of these agents was not additive. This suggested that a labile protein was involved in processing bFGF mRNA. Determination of message stability indicated that the half-life of bFGF mRNA in TGFbeta1-treated PS was 6.8 hr, as compared to 4.3 hr in untreated cells. The data indicated that posttranscriptional mechanisms that increased message stability were, at least in part, responsible for upregulation of bFGF mRNA by TGFbeta1 in PS. Our studies suggest that growth of the prostatic stroma is regulated by the interaction of members of two families of growth modulators, bFGFand TGFbeta. It remains to be determined if an imbalance in this system in favor of stroma hyperplasia plays a role in the development of BPH.

Expression of mRNA for vasoactive intestinal peptide in rat small intestine.

Transplantation of small intestine is a neural model that permits studies of expression of the neuropeptide, vasoactive intestinal peptide, following extrinsic denervation, transection of intrinsic neural pathways, and an ischemic interval. Tissue levels of vasoactive intestinal peptide were examined at 3 months in ileum from a sham operation, in ileum after resection of proximal small intestine, in ileum after resection of proximal small intestine and extrinsic denervation, in ileum after resection of proximal small intestine and 30 min of ischemia, and in ileum obtained 3 months after ileal isografting in Lewis-to-Lewis combinations. Vasoactive intestinal peptide levels were increased in transplanted rat ileum, resection controls, denervation controls, and ischemic controls compared to sham-operated ileum (pANOVA < 0.01). The increased levels of this peptide were highest in denervation controls and lowest in ischemic controls. Northern blot analysis using rat vasoactive intestinal peptide cDNA identified a single 1.7-kb transcript in normal and transplanted rat ileum. The density of vasoactive intestinal peptide transcripts was increased in transplanted ileum (8450 +/- 540) compared to normal ileum (5790 +/- 620) (P < 0.01), and the ratio of this transcript to glyceraldehyde-3-phosphate dehydrogenase density units was also increased in transplanted ileum (0.81 +/- 0.08) compared to normal ileum (0.40 +/- 0.07; P < 0.01). Enhanced transcriptional regulation was the likely mechanism for increased tissue vasoactive intestinal peptide. The increased tissue levels appeared to be a response to extrinsic denervation and transection of intrinsic neural pathways, while an ischemic interval appeared to decrease tissue levels of the peptide.

Cervical lymph node metastasis of thyroid papillary carcinoma imaged with fluorine-18-FDG, technetium-99m-pertechnetate and iodine-131-sodium iodide.

A 49-yr-old white woman with diffuse sclerosing variant of papillary carcinoma of the thyroid revealed abnormal [18F]FDG accumulation within cervical lymph node metastases prior to thyroidectomy. The abnormal cervical foci of glucose metabolism corresponded to similar areas of abnormal [99mTc]pertechnetate and radioiodine accumulation on presurgical scans. The primary thyroid tumor within the thyroid gland was not delineated as a focal defect on any of the three imaging studies. The relative thyroid-to-background soft-tissue ratio in the [18F]FDG study, however, appeared higher than usual. As with 131I and [99mTc]pertechnetate, this case demonstrates that [18F]FDG PET can detect cervical lymph node metastases in the preoperative thyroid cancer patient.

Effects of obesity and gender on insulin receptor expression in liver of SHHF/Mcc-FAcp rats.

In SHHF/Mcc-FAcp rats (formerly SHR/Mcc-cp), obesity and male gender synergistically modulate hyperinsulinemia, insulin resistance and predisposition to diabetes. Our previous studies showed gender and obesity modulate hepatic cell surface insulin binding and insulin clearance additively. Hepatic insulin receptors (IR) bind insulin as a first step in insulin clearance through internalization and degradation. We hypothesize that the synergistic effects of obesity and gender on hepatic insulin binding and clearance result from interaction of these two factors on hepatic IR expression. To address IR expression in SHHF/Mcc-FAcp rats, we quantitated IR protein levels in detergent-solubilized liver homogenates by Western blotting and IR mRNA levels by a solution hybridization/RNase protection assay. Obesity reduced total hepatic IR content in males and females, 50% and 68% respectively. Male gender reduced IR protein content 24% in lean, but had no effect on IR protein content in obese rats. Neither gender nor obesity affected hepatic IR mRNA content. Thus, obesity appears to affect hepatic IR protein content and cell surface binding through post-transcriptional mechanisms; similarly, male gender in lean rats reduces IR protein levels and cell surface binding through mechanisms not involving changes in mRNA levels. In obese rats, the synergistic effects of male gender appears to involve changes in IR trafficking and consequently cell surface insulin binding and processing.

Endothelial dysfunction in a model of hyperglycemia and hyperinsulinemia.

Insulinopenic diabetes is known to produce endothelial dysfunction. This dysfunction could arise from either hyperglycemia or inadequate insulin. It is not known whether endothelial dysfunction occurs when hyperglycemia is present with elevated insulin levels. In this study, we utilized an experimental model of hyperglycemia with hyperinsulinemia to investigate latent endothelial dysfunction. Rats were continuously infused with glucose or saline for 72 h to achieve peak plasma glucose concentrations of approximately 25 mM. Plasma insulin rose by 12-fold in glucose-infused rats. No significant differences in serum electrolyte concentration were noted between control and glucose-infused rats after 72 h. Blood pressure was not altered by this intervention. Aortic rings taken from control rats relaxed to the endothelium-dependent vasodilators, acetylcholine and A-23187, and to the endothelium-independent vasodilator, nitroglycerin. Relaxation to acetylcholine but not to A-23187 or nitroglycerin was impaired in glucose-infused rat aortic rings. Incubation in vitro with either indomethacin or superoxide dismutase did not restore the impaired relaxation to acetylcholine in rings taken from glucose-infused rats. Thus hyperglycemia with hyperinsulinemia selectively impairs receptor-dependent, endothelium-dependent relaxation. These studies suggest that elevated glucose may be a common pathway leading to endothelial dysfunction in insulin-dependent diabetes mellitus and hyperglycemia-induced insulin resistance.

Advances in the management of patients with thyroid disease.

Discoveries related to thyroid immunology, especially concerning the thyroid-stimulating hormone (TSH) receptor, may facilitate new immunologic approaches to the therapy of Graves' disease and the thyroiditis syndromes. Advances in genetics are being applied to the thyroid hormone resistance syndromes and papillary and medullary carcinomas. The development of ever more sensitive TSH assays has led to the detection of subclinical thyroid disease, which has special implications for the sick and elderly patients. Sensitive TSH assays also allow more precise titration of levothyroxine (T4) dosages, especially for patients with a past history of thyroid cancer. Evidence continues to accumulate suggesting that postmenopausal women on T4 doses that suppress the TSH level below 0.1 ulU/mL have lower bone mineral density than matched patients with healthy TSH levels. Also, pregnant hypothyroid women need higher T4 doses to normalize the TSH levels. In the evaluation of thyroid nodules, fine-needle aspiration biopsy is the single most definitive modality in selecting the patients for surgery. Scintigraphy provides a complimentary role, especially in defining autonomously functioning thyroid adenomas (AFTA), because these should not be treated with T4 suppression. Ultrasound-guided needle biopsy is occasionally helpful with nodules that are difficult to palpate. Concern for possible tracheal compression after treatment of toxic multinodular goiter with large doses of radioactive iodine (I-131) in the range of 50 to 150 mCi (1.85 to 5.5 GBq) does not seem warranted. Work, primarily out of Italy, suggests AFTA can be ablated with repeat ethanol injections. Residual tissues after thyroidectomy for differentiated carcinoma can be "stunned" by tracer doses of 131I greater than 3.0 mCi (111 MBq), which diminishes the uptake and effectiveness of a subsequent therapy dose. Positron emission tomograph, imaging with thallium-201, and Technetium 99m Sestamibi can identify a small number of patients shown to have metastases from differentiated thyroid carcinoma by increasing thyroglobulin levels in the absence of 131I uptake. Several groups have recently advocated treating such patients empirically with 131I.

Estrogen receptor binding to DNA: affinity for nonpalindromic elements from the rat prolactin gene.

The estrogen receptor (ER) binds with high affinity to the nonclassical estrogen response elements (ERE) found in the rat prolactin gene. There are two putative EREs in this gene; at -1582 and -1722 upstream of the transcriptional start site. We used DNA binding assays based on the immunoprecipitation of receptor with bound DNA to quantitate the binding of ER to these two elements. ER bound each element with significantly higher affinity than it bound to nonspecific DNA, but with 10-100-fold less affinity than that for the classical ERE sequence derived from the vitellogenin A2 gene. These comparisons rank the prolactin gene sequences as weak EREs. We also observed a 1:1 ratio of ER to ERE in the bound complexes, indicating that these high-affinity interactions were not dependent upon an ER homodimer. These data support the role of these sequences in mediating estrogen regulation of the prolactin gene.

Expression of mRNA for vasoactive intestinal peptide in normal human colon and during inflammation.

The availability of colon provides a ready source of human neurons. Among the products of nerve cell bodies, vasoactive intestinal peptide is a neuropeptide that serves as a marker of non-adrenergic, non-cholinergic inhibitory nerves in colon. These nerves have been proposed to be involved in regulation of immune function, secretion, and smooth muscle function. In previous work, we identified decreased tissue levels of vasoactive intestinal peptide in a disorder of chronic colonic mucosal inflammation, ulcerative colitis. We hypothesized that diminished gene expression of vasoactive intestinal peptide could result in decreased tissue levels of this neuropeptide. Sigmoid colon was obtained at surgery from controls (n = 6) and patients with ulcerative colitis (n = 6). Vasoactive intestinal peptide mRNA was quantified by Northern blot hybridization and tissue levels of vasoactive intestinal peptide were determined by radioimmunoassay. Tissue vasoactive intestinal peptide was decreased only in the mucosal-submucosal layer of ulcerative colitis (p = .02). There was a single 1.7 kbase vasoactive intestinal peptide transcript identified in both control colon and ulcerative colitis. Normalized vasoactive intestinal peptide mRNA levels were increased by 260% in ulcerative colitis compared to controls (p < .01). These observations suggest that decreased vasoactive intestinal peptide gene expression or abnormal post-transcriptional processing are not primary defects in this disorder of chronic inflammation. The findings support the alternative hypothesis that axonal degeneration in ulcerative colitis could result in increased expression of neuronal vasoactive intestinal peptide mRNA.

Vasoactive intestinal polypeptide antiserum affects rat prolactin mRNA in 40-day but not 110-day diethylstilbestrol-induced prolactinoma tissue.

Experiments were designed to examine whether vasoactive intestinal polypeptide (VIP), a known stimulator of basal prolactin (PRL) secretion, regulates PRL gene expression in the rat diethylstilbestrol (DES)-induced prolactinoma model. The VIP-induced increase in PRL release could result from increased PRL synthesis and/or decreased PRL degradation. Male Fischer 344 rats were implanted with 10 mg DES pellets 40 or 110 days prior to obtaining the anterior pituitary glands for cell dispersal. Cells were incubated in 1:10 normal rabbit serum or VIP antiserum (AVIP). After incubation, cells were pelleted, washed, and pooled for total nucleic acid extraction. The rat PRL (rPRL) mRNA abundance was quantitated using a solution hybridization/ribonuclease protection assay. Supernatant was collected and analyzed for PRL content using radioimmunoassay. Results from this experiment reveal partial immunoneutralization of intrapituitary VIP significantly decreased PRL secretory rate by rapid reduction in rRPL mRNA in the 40-day tumors. However, in the 110-day tumors the rPRL mRNA steady-state levels were unchanged but the basal release of PRL continued to be decreased by AVIP. These results indicate VIP exerts its effects on PRL secretion through at least two mechanisms.

Characteristics of FGF-receptors expressed by stromal and epithelial cells cultured from normal and hyperplastic prostates.

Three fibroblast growth factors (FGFs), acidic FGF (FGF1), basic FGF (FGF2), and keratinocyte growth factor (FGF7) have been identified in prostate. To understand how FGFs regulate growth of the prostate, and to determine if regulation is altered in benign prostatic hyperplasia (BPH), the mitogenic potential of FGFs, receptor binding, and FGF-receptor (FGFR) gene expression of stromal (PS) and epithelial cells (PE) cultured from normal human prostate and BPH where determined. FGF1 and FGF2, but not FGF7, were mitogens for PS. FGF1 and FGF7 were potent mitogens for PE, but FGF2 was a weak mitogen for these cells. Both PS and PE exhibited high affinity binding (pM K) of iodinated-FGF2. The K was 4-fold and 12-fold higher for PS than for PE cultured from normal prostate and BPH, respectively. Northern analysis indicated that PS, but not PE, expressed FGFR type 1 (FGFR1) mRNA. The reverse transcriptase polymerase chain reaction (RT-PCR) was used to evaluate FGFR type 2 (FGFR2) expression. The size of amplified DNA fragments, and nucleotide sequences, indicated that PS also expressed transcripts for the exon IIIc RNA splice variant of FGFR2. A RT-PCR product with the FGFR2 exon IIIb nucleotide sequence joined with the exon IIIc sequence was amplified with poly A+ RNA from PE and primers spanning both exons. Thus, PE did not alternatively splice mRNA for FGFR2 exon IIIb and exon IIIc. No differences in the mitogenic potential of FGFs, receptor binding (K or number of sites), or FGFR gene expression were found in cells cultured from normal prostate and BPH.

Gene expression and transcript size of the prepro-peptide VIP/PHM-27 in normal human tissue.

The transcript size of VIP/PHM-27 mRNA (vasoactive intestinal peptide/peptide histidine methionine) and the relative distribution of VIP/PHM-27 gene expression in 10 normal human tissues was examined. After mRNA extraction from tissue, VIP/PHM-27 transcript size and relative abundance of mRNA was determined by Northern blot analysis and densitometry of the autoradiograms. VIP/PHM-27 mRNA was detectable in brain, pancreas, colon, ileum and striated muscle while no hybridization signal was observed in liver, kidney, lung, heart, prostate and placental tissue. VIP/PHM-27 transcript in human brain and gut was a single band of 1.7 kb; by contrast, a 7.0-kb transcript was detected in striated skeletal muscle. The highest relative levels of mRNA were observed in brain and pancreas.

Female sex hormones, perinatal, and peripubertal androgenization on hepatocyte insulin dynamics in rats.

The effects of female sex hormones on insulin binding and receptor-mediated insulin degradation were investigated in hepatocytes from ovariectomized rats. The influences of perinatal and peripubertal androgenization on these events were examined. Estradiol treatment increased insulin binding and receptor-mediated insulin degradation by increasing cell surface insulin receptor number. Progesterone also increased both binding and degradation, but the increase in degradation exceeded the increase in binding. Perinatal exposure to testosterone blunted the estradiol-induced increase in insulin binding and decreased degradation, whereas the progesterone-mediated increases were completely suppressed. Peripubertal testosterone decreased binding, with a much greater reduction in insulin degradation. Perinatal androgenization did not influence the peripubertal testosterone effects. Thus peripubertal female sex hormones exert regulatory influences on both hepatic cell surface insulin receptor number and postreceptor events mediating insulin degradation. These events are modulated by perinatal and peripubertal exposure to androgens. Abnormalities in sex hormone levels and/or hepatic androgenization could therefore contribute to altered insulin metabolism and hyperinsulinemia in some hyperandrogenized women with abdominal obesity and increased androgenic activity.

Influence of transforming growth factor beta 1 and other growth factors on basic fibroblast growth factor level and proliferation of cultured human prostate-derived fibroblasts.

Basic fibroblast growth factor (bFGF) has been identified in the human prostate. The level of bFGF has been reported to be elevated in benign prostatic hyperplasia (BPH), compared with normal prostate, suggesting that the growth factor may play a role in this disease of the prostate. Basic FGF is a mitogen for cultured human prostate-derived fibroblasts (PF). PF also synthesize bFGF, suggesting that growth regulation of these cells may be under autocrine control. The current study was undertaken to identify factors that affect PF proliferation and bFGF expression. Transforming growth factor beta 1 (TGF-beta 1) inhibited PF proliferation. The inhibition by TGF-beta 1 was partially overcome by bFGF but not by epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor type 1 (IGF-1), or insulin. Incubation of PF with TGF-beta 1 increased bFGF mRNA and immunoreactive bFGF levels in a dose- and time-dependent fashion. None of the other growth factor studies affected bFGF levels. PF were also found to express TGF-beta 1 mRNA, the level of which was increased two- to fivefold by TGF-beta 1. These observations suggest that PF proliferation is controlled by the interaction of two different growth factors. It is possible that bFGF/TGF-beta imbalance in favor of cell proliferation promotes prostatic stromal hyperplasia.