2013 European thyroid association guidelines for cervical ultrasound scan and ultrasound-guided techniques in the postoperative management of patients with thyroid cancer.

Cervical ultrasound scanning (US) is considered a key examination, by all major thyroid and endocrine specialist societies for the postoperative follow-up of thyroid cancer patients to assess the risk of recurrence. Neck US imaging is readily available, non-invasive, relatively easy to perform, cost-effective, and can guide diagnostic and therapeutic procedures with low complication rates. Its main shortcoming is its operator-dependency. Because of the pivotal role of US in the care of thyroid cancer patients, the European Thyroid Association convened a panel of international experts to review technical aspects, indications, results, and limitations of cervical US in the initial staging and follow-up of thyroid cancer patients. The main aim is to establish guidelines for both a cervical US scanning protocol and US-guided diagnostic and therapeutic procedures in patients with thyroid cancer. This report presents (1) standardization of the US scanning procedure, techniques of US-guided fine-needle aspiration, and reporting of findings; (2) definition of criteria for classification of malignancy risk based on cervical US imaging characteristics of neck masses and lymph nodes; (3) indications for US-guided fine-needle aspiration and for biological in situ assessments; (4) proposal of an algorithm for the follow-up of thyroid cancer patients based on risk stratification following histopathological and cervical US findings, and (5) discussion of the potential use of US-guided localization and ablation techniques for locoregional thyroid metastases.

Comparison of efficacy of 2220 MBq versus 3700 MBq I-131 for ablation of thyroid remnant in patients with differentiated thyroid cancer.

AIM: We evaluated the efficacy of two doses of I-131 (2220 MBq versus 3700 MBq) after thyroid hormone withdrawal for thyroid remnant ablation postoperatively in patients with differentiated thyroid cancer (DTC). METHODS: A total of 133 patients with DTC were studied retrospectively. Group 1 (N.=48) included patients with a primary tumor less than 4 cm in mean diameter and confined to the thyroid gland that received an average ablation dose of 2220 MBq. Group 2 (N.=81) included patients with a primary tumor equal to or greater than 4 cm in mean diameter and/or with vascular invasion and/or intrathyroidal lymphovascular invasion and/or microscopic extrathyroidal extension that received an average ablation dose of 3700 MBq. There was no significant difference between the two groups in terms of demographic characteristics or the radioiodine uptake in the neck (2.86+2.31% versus 2.84+1.21%, P=0.97). The success of the remnant ablation was judged by the standard institutional protocol: I-123 whole body scan (WBS) and serum Thyroglobulin (Tg) level after thyroid hormone withdrawal or preparation with recombinant human TSH (rhTSH) 6-12 months after ablation. RESULTS: Overall, remnant ablation was successful in 121/133 (91%) patients. There was no statistically significant difference in the success of ablation between Group 1 and Group 2 (87.5% versus 93%, P=0.273). CONCLUSION: Therefore, for thyroid remnant ablation after thyroid hormone withdrawal, an administered I-131 dose of 2220 MBq is just as effective as 3700 MBq and has the potential for fewer longterm side effects.

The role of MR imaging in detecting nodal disease in thyroidectomy patients with rising thyroglobulin levels.

BACKGROUND AND PURPOSE: One of the dilemmas facing clinicians treating patients with thyroid cancer is the evaluation of postthyroidectomy patients with rising serum thyroglobulin levels and indeterminate or normal findings on neck sonography. In this study, we examine the role of MR imaging in this subgroup of patients. MATERIALS AND METHODS: We retrospectively reviewed MR images of patients with thyroid cancer with abnormal lymph nodes in the retropharyngeal and parapharyngeal spaces and determined the size and signal-intensity characteristics of these nodes. We reviewed patient charts for the following history: 1) thyroidectomy, 2) rising thyroglobulin levels, 3) iodine-131 radiation therapy, 4) neck dissection, and 5) pathology on neck sonography and chest CT. We reviewed pathology findings to determine if thyroid cancer metastases were present in these lymph nodes. RESULTS: Eight patients had abnormal retropharyngeal space nodes, and 1 patient had a parapharyngeal space mass. Lymph nodes ranged from 7 to 25 mm. On MR imaging, 1 patient had a cystic node, 2 had complex nodes, and 6 had solid nodes. Eight patients had rising serum thyroglobulin levels and a history of thyroidectomy, radioiodine therapy, and neck dissection. Two of these patients had no pathologic nodes on sonography and normal findings on chest CT. Six patients had tissue sampling of their skull base node, and metastatic thyroid cancer was present in 5. CONCLUSIONS: MR imaging of the neck should be considered in thyroidectomy patients with rising serum thyroglobulin levels and a history of radioiodine therapy and neck dissection. Radiologists should carefully examine the retropharyngeal and parapharyngeal spaces in these patients because nodal metastases may occur there more commonly than realized.

Interinstitutional review of thyroid fine-needle aspirations: impact on clinical management of thyroid nodules.

Routine interinstitution pathology consultation can result in change in pathologic diagnosis in up to 10% of patients. In this study, we compared the outside cytopathologic diagnosis of thyroid fine-needle aspiration (FNA) specimens with the in-house diagnosis at the University of Pennsylvania Medical Center over an 18-mo period and its effect on patient management. One hundred ten (60%) diagnostic disagreements were identified among 183 patients. In 16 cases, the diagnosis was changed from benign to malignant, and in 12, the diagnosis was reversed from neoplastic/malignant to benign. Histologic follow-up was available in 109 cases; the overall accuracy of outside diagnosis was 73%, and that of inside diagnosis was 85%. In conclusion, we strongly recommend interinstitution cytology consultation on referred thyroid FNA cases, since our data showed a significant change in diagnosis, thus affecting patient management.

Thyroid papillary microcarcinoma. Is it really a pitfall of fine needle aspiration cytology?

OBJECTIVE: To assess the role of fine needle aspiration (FNA) of the thyroid in the diagnosis of papillary microcarcinoma. STUDY DESIGN: Eight cases of papillary microcarcinoma were diagnosed by fine needle aspiration. On histologic examination they were found to be adjacent to larger nodules of interest. The microcarcinomas were inadvertently sampled when sampling the larger, dominant nodules. RESULTS: None of the eight dominant nodules were papillary carcinoma; seven were benign lesions, and one was an angioinvasive Hürthle cell carcinoma. In three cases the microcarcinomas were situated within the capsule of a hyperplastic nodule. On histologic examination, five cases had multifocal microcarcinomas, with one case having multiple lymph node metastases. Based on the clinical findings and morphologic features, there were no definitive cytologic findings that could distinguish between "incidental" microcarcinoma and clinically significant papillary carcinoma. CONCLUSION: The detection of microcarcinoma by FNA should not be considered a false positive finding since the exact nature of the lesion cannot be determined until complete histologic evaluation reveals it to be truly incidental and clinically insignificant.

Sonographic appearance of focal thyroiditis.

OBJECTIVE: The purpose of this study is to report the sonographic appearance of focal thyroid nodules that prove to be lymphocytic thyroiditis on fine-needle aspiration. CONCLUSION: In a patient population undergoing sonography for palpable nodular disease without known thyroiditis, focal nodules of thyroiditis had a wide variety of appearances. They most commonly appeared as solid hyperechoic nodules with ill-defined margins. However, the echogenicity was variable, and calcification and cystic-appearing regions were also noted. The vascularity of these nodules as assessed with color Doppler and power Doppler sonography also varied widely. Biopsy of these lesions is still necessary because there are no sonographic features that can reliably diagnose these lesions as thyroiditis and differentiate them from other lesions.

Superiority of iodine-123 compared with iodine-131 scanning for thyroid remnants in patients with differentiated thyroid cancer.

PURPOSE: Iodine-123 is a pure gamma emitter and has excellent characteristics for imaging with modern scintillation cameras. The goal of this study was to compare the performance of I-123 and I-131 as imaging agents for whole-body scanning in patients with differentiated thyroid cancer undergoing ablation for thyroid remnants after initial surgery. METHODS: Fourteen patients with differentiated thyroid cancer who had undergone near-total thyroidectomy and had serum thyroid-stimulating hormone levels greater than 40 mU/I underwent diagnostic scanning 5 hours after administration of 48 to 56 MBq (1.3 to 1.5 mCi) I-123 and 48 hours after administration of 111 MBq (3 mCi) I-131. After receiving ablative I-131 therapy, they also underwent whole-body planar imaging 7 days later. The diagnostic I-123 and I-131 scans were compared with each other and with the post-therapy images by two nuclear medicine physicians and one endocrinologist. RESULTS: The diagnostic scans revealed 35 foci in the thyroid bed and neck. The I-123 images showed all 35 foci, but only 32 of the 35 foci (91 %) were seen on the I-131 scans. The findings of pre- and post-therapy scans were concordant in 11 of 13 patients, and the same general sites of uptake (left and right thyroid bed, midline) were revealed on both sets of images. In one patient, a focus seen on the diagnostic I-123 and I-131 images was not visualized on the post-therapy scan and was thought to represent possible stunning. An additional area of uptake in the lower right neck and upper mediastinum was present on the post-therapy scan of another patient, but it was not seen on diagnostic images. CONCLUSION: These results show improved quality of imaging with 50 MBq (1.5 mCi) I-123 compared with 111 MBq (3 mCi) I-131 for whole-body scanning in patients with differentiated thyroid cancer undergoing thyroid remnant ablation. I-123 imaging may prove to be the preferred procedure in such settings in patients with differentiated thyroid cancer.

Usefulness of ultrasonography in the management of nodular thyroid disease.

BACKGROUND: Fine-needle aspiration biopsy is the standard diagnostic test for evaluating possible malignancy in a thyroid nodule. OBJECTIVE: To evaluate the role of routine ultrasonography in the management of nodular thyroid disease. DESIGN: Retrospective chart review. SETTING: Multidisciplinary thyroid nodule clinic (endocrinology and radiology). PATIENTS: Patients with suspected nodular thyroid disease or suspected recurrent thyroid cancer referred between October 1995 and March 1997. All patients had thyroid ultrasonography and ultrasonography-guided fine-needle aspiration biopsy of nodules at least 1 cm in maximum diameter. MEASUREMENTS: Medical records, ultrasonography findings, cytology reports, and histologic reports were reviewed. Ultrasonography findings were compared with the referring physician's findings on physical examination. RESULTS: 223 patients were seen in the clinic. A total of 209 fine-needle aspiration biopsies were performed on 156 patients. Among 50 of 114 patients referred for a solitary nodule, ultrasonography detected additional nonpalpable nodules at least 1 cm in diameter in 27 and determined that no nodules required aspiration in 23. Of 59 patients referred for a diffuse goiter or a multinodular gland, ultrasonography detected discrete nodules at least 1 cm in diameter that required aspiration in 39 and determined that aspiration was unnecessary in 20. CONCLUSIONS: Ultrasonography altered the clinical management for 63% of the patients (109 of 173) referred to the thyroid nodule clinic after abnormal results on thyroid physical examination.

Atypical hypothyroidism and the very low birthweight infant.

Results of thyroid screening tests were examined retrospectively on 311,282 infants born in Massachusetts from January 1, 1993 to December 31, 1996. During this period, 118 infants were found to have typical hypothyroidism, characterized by a low thyroxine (T4) and an elevated thyrotropin (TSH) on the initial newborn-screening specimen. Of these, 98 were normal birthweight (NBW, > or = 2,500 g), 9 were low birthweight (LBW, 1,501-2,499 g), and 11 were very low birthweight (VLBW, < or = 1,500 g). Atypical hypothyroidism as defined here is characterized by a low T4 and normal TSH concentration on the initial screening specimen, followed by and elevated TSH level on a repeat blood specimen. This phenomenon occurred in 18 infants, of whom 4 were NBW, 4 were LBW, and 10 were VLBW. The incidence of combined typical and atypical hypothyroidism was: NBW, 1:3051; LBW, 1:1589; VLBW, 1:153, with the highest incidence of atypical hypothyroidism in the VLBW category (48% of cases in this weight category, 56% of all cases of atypical hypothyroidism). In addition, screening programs using a primary TSH screen will miss infants with atypical hypothyroidism. In view of these results, it is suggested that T4 measurements be obtained routinely in all LBW and VLBW infants, with additional routine repeat blood specimens.

Thyroiditis after pregnancy loss.

We present a case series evaluating the development and characteristics of thyroiditis following pregnancy loss. Five women were followed prospectively with measurement of thyroid function and antithyroid antibodies after pregnancy loss. Serum TSH concentrations were measured by immunoradiometric assay and antithyroid antibodies by RIA and hemagglutination techniques. All women had normal serum TSH concentrations before conception or at the time of pregnancy loss, and all but one had positive antithyroid antibodies. Pregnancy loss occurred between 5-20 weeks gestation because of ectopic pregnancy or either spontaneous or elective abortion. Two women had subclinical hypothyroidism with peak serum TSH values of 8.7 mU/L and 5.4 mU/L at 2 and 7 months after pregnancy loss, respectively. Three women had clinical hyperthyroidism with serum TSH values < or = 0.2 mU/L diagnosed between 3-11 months after pregnancy loss followed subsequently by a hypothyroid phase. Painless thyroiditis within 1 yr of pregnancy loss in these women suggests that the immunological changes of a short-term gestation may be sufficient to lead to thyroiditis.

Prospective studies of thyroid function in patients receiving gold therapy.

Gold inhibits the Type I deiodinase that provides the bulk of circulating T3 in humans. We prospectively studied thyroid function in patients receiving increasing parenteral cumulative gold doses. Eight consecutive euthyroid patients with rheumatoid or psoriatic arthritis who were initiating intramuscular gold therapy were enrolled. Serum thyroid hormone levels (total T4, T3, and rT3) and TSH were measured for each subject at various levels during gold therapy. For analysis, the free T4 and free T3 indices, TSH concentrations, and T4/T3 ratios were correlated with cumulative gold dose. Neither individual nor pooled linear regressions showed a significant correlation between cumulative gold dose and any of the thyroid function parameters. Thyroid function is not affected in patients receiving up to 1500 mg of gold compounds. The most likely explanation for this is that gold principally accumulates in the Kupffer cells and renal cortex and these cells do not express Type I deiodinase.

Review of antithyroid drug use during pregnancy and report of a case of aplasia cutis.

Thioamide therapy has improved the outcome of pregnancies complicated by maternal hyperthyroidism, without long-term effects on cognitive and somatic development. However, there remain questions concerning whether these drugs, especially methimazole (MMI), may be associated with aplasia cutis congenita (ACC) and how best to avoid impairment of fetal thyroid function during their use. We report an example of ACC and review the relevant literature. We conclude that there is insufficient evidence either to establish or eliminate a direct causal relationship between ACC and MMI use. Since propylthiouracil is an equally effective antithyroid agent and has not been associated with ACC, it is the preferred thioamide for hyperthyroidism during pregnancy. Our review also indicates that impairment of neonatal thyroid function may be minimized by using a thioamide dose that is just sufficient to maintain the maternal serum free thyroxine concentration in the high normal or slightly thyrotoxic range.

Levothyroxine therapy in patients with thyroid disease.

PURPOSE: To review the indications for and the proper monitoring of levothyroxine therapy in patients with thyroid disease. DATA SOURCES: Relevant English language articles published from 1966 to 1992 were identified through a MEDLINE search and manual searches of both identified articles and selected endocrinology texts. STUDY SELECTION: Studies, case reports, and review articles that contained data on the pathophysiologic aspects of relevant thyroid disorders and on the pharmacologic aspects of, indications for, and administration of levothyroxine therapy. DATA EXTRACTION: Data on the epidemiology, clinical manifestations, complications, and treatment of thyroid disorders were analyzed with respect to patient selection, methods, diagnostic criteria, and conclusions. These data were used to develop a rational approach to the management of such patients. RESULTS OF DATA SYNTHESIS: Levothyroxine is a reliable and commonly prescribed drug to treat thyroid disease, but excessive dosage may have adverse effects. In patients with hypothyroidism, levothyroxine is used as replacement therapy. For most patients, therapy can be initiated with a full replacement dosage (1.6 micrograms/kg body weight), which is usually 75 to 100 micrograms/day for women and 100 to 150 micrograms/d for men. The goal is to normalize the serum thyroid-stimulating hormone concentration. Levothyroxine is also used to suppress the serum thyroid-stimulating hormone concentration. A trial of thyroid-stimulating hormone suppressive therapy is indicated for most patients with benign solitary nonfunctioning thyroid nodules and for those with a history of thyroid cancer. Levothyroxine in non-thyroid-stimulating hormone-suppressive doses may also be indicated for patients with nontoxic multinodular goiter and for certain patients after lobectomy for benign thyroid nodules. CONCLUSIONS: With proper patient monitoring, levothyroxine replacement therapy should be effective, inexpensive, and free of complications. Recommendations for thyroid-stimulating hormone suppression with levothyroxine are based on risk-benefit considerations of the biologic characteristics of the thyroid disorder and the individual patient.

Cloning and in vitro expression of the human selenoprotein, type I iodothyronine deiodinase.

The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. We have recently cloned the complementary DNA (cDNA) for the rat 5' DI, which contains the rare amino acid selenocysteine, and used this to screen human liver and kidney cDNA libraries to identify a human 5' DI cDNA clone. From these, we constructed a cDNA encoding a functional 5' DI. The 2222 base pair human 5' DI cDNA is approximately 200 nucleotides shorter than the 2.4-kilobase hybridizing band in Northern blots of human liver, kidney, and thyroid, because of missing 5' untranslated sequence and the poly A tail. The deduced amino acid sequence codes for a protein of 28.7 kilodaltons assuming the UGA codon at position 382 encodes selenocysteine, and is highly homologous (88% similarity) to the rat. We transiently expressed the 5' DI in COS-7 cells to establish that it encodes a functional enzyme and to study its kinetics. These show saturable deiodination of rT3 (Ka 0.52 +/- 0.04 mumol/L and Vmax 63.2 +/- 16.4 pmol min-1 mg-1). T4 and gold thioglucose are competitive inhibitors of rT3 deiodination. 6-n-Propylthiouracil (PTU) is an uncompetitive inhibitor (with rT3) and competitive inhibitor (with dithiothreitol) of rT3 deiodination. 6-n-Propylthiouracil inhibits T4 to T3 conversion. Labeling of COS-7 cells transiently transfected with the human 5' DI cDNA with bromoacetyl-125I-T3 demonstrates a 28-kilodalton protein. This indicates that in the human, as well as in the rat messenger RNA, the UGA encodes selenocysteine and translation terminates at the UAA codon at nucleotides 754 to 756. Reverse T3 and gold thioglucose (100 nmol/L) block bromoacetyl-125I-T3 labeling of the transiently expressed human and rat 5' DI proteins. These results demonstrate that the human 5' DI is a selenoprotein, analogous to the rat enzyme. Given the previously demonstrated critical role of the selenium atom in catalyzing deiodination by this protein, we conclude that this trace element is essential for normal thyroid hormone action in man.

Interrelationships between the renin-angiotensin-aldosterone and calcium homeostatic systems.

Blood pressure is affected by both sodium and calcium intake. To determine if there is an interaction between the regulatory mechanisms for these two cations, eight normal male volunteers received the following 1-h infusions on three different days: 1) angiotensin II (AII), 2) the synthetic 1-34 amino terminal fragment of human PTH [hPTH(1-34)], and 3) AII and hPTH(1-34) together. Blood samples were obtained at t = 0 and every 20 min during each infusion and urine was collected for 3 h both before and after the start of each infusion. Infusion of AII produced an increase in intact PTH from 18 +/- 2 to 31 +/- 4 ng/L (P < 0.05), most likely in response to a small decrease in serum ionized calcium (1.25 +/- 0.01 to 1.23 +/- 0.01 mmol/L, P < 0.05). Urinary excretion of calcium was unchanged. Infusion of hPTH(1-34) at 200 U/h increased N-terminal PTH levels (18 +/- 3 to 268 +/- 42 ng/L, P < 0.05), decreased tubular reabsorption of phosphate (0.92 +/- 0.03 to 0.82 +/- 0.11, P < 0.05), and increased urinary cAMP (0.18 +/- 0.02 to 0.53 +/- 0.05 nmol/L of glomerular filtrate, P = 0.0001). hPTH(1-34) infusion suppressed endogenous intact PTH (18 +/- 3 to 14 +/- 2 ng/L, P < 0.005) and increased PRA from 0.14 +/- 0.02 to 0.32 +/- 0.05 ng/(L.s) (P < 0.05) without a change in serum ionized calcium which suggests direct effects of hPTH(1-34) on the parathyroid glands and the juxtaglomerular apparatus. The effects of AII and hPTH(1-34) were antagonistic with little change in serum ionized calcium, intact PTH, or PRA when both were infused together. These interrelationships between the major hormonal systems controlling sodium and calcium homeostasis suggest a mechanism underlying the close association of calcium and sodium in the regulation of blood pressure.

Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3' untranslated region.

Selenocysteine is incorporated cotranslationally at UGA codons, normally read as stop codons, in several bacterial proteins and in the mammalian proteins glutathione peroxidase (GPX), selenoprotein P and Type I iodothyronine 5' deiodinase (5'DI). Previous analyses in bacteria have suggested that a stem-loop structure involving the UGA codon and adjacent sequences is necessary and sufficient for selenocysteine incorporation into formate dehydrogenase and glycine reductase. We used the recently cloned 5'DI to investigate selenoprotein synthesis in eukaryotes. We show that successful incorporation of selenocysteine into this enzyme requires a specific 3' untranslated (3'ut) segment of about 200 nucleotides, which is found in both rat and human 5'DI messenger RNAs. These sequences are not required for expression of a cysteine-mutant deiodinase. Although there is little primary sequence similarity between the 3'ut regions of these mRNAs and those encoding GPX, the 3'ut sequences of rat GPX can substitute for the 5'DI sequences in directing selenocysteine insertion. Computer analyses predict similar stem-loop structures in the 3'ut regions of the 5'DI and GPX mRNAs. Limited mutations in these structures reduce or eliminate their capacity to permit 5'DI translation. These results identify a 'selenocysteine-insertion sequence' motif in the 3'ut region of these mRNAs that is essential for successful translation of 5'DI, presumably GPX, and possibly other eukaryotic selenocysteine-containing proteins.

Increased need for thyroxine during pregnancy in women with primary hypothyroidism.

BACKGROUND AND METHODS: Women with hypothyroidism have been thought not to require an increase in thyroxine replacement during pregnancy. To evaluate the effects of pregnancy on thyroxine requirements, we retrospectively reviewed the thyroid function of 12 women receiving treatment for primary hypothyroidism before, during, and after pregnancy. RESULTS: In all patients, the serum thyrotropin level increased during pregnancy. The mean (+/- SE) serum free-thyroxine index decreased from 111.0 +/- 5.8 before pregnancy to 86.5 +/- 5.2 during pregnancy (normal, 64 to 142; P less than 0.05), and the mean serum thyrotropin level increased from 2.0 +/- 0.5 mU per liter before pregnancy to 13.5 +/- 3.3 mU per liter during pregnancy (normal, 0.5 to 5.0 mU per liter; P less than 0.01). Because of high thyrotropin levels, the thyroxine dose was increased in 9 of the 12 patients. Among the three patients who did not require an increased thyroxine dose were two with low serum thyrotropin levels before pregnancy, suggesting excessive replacement at that time. The mean thyroxine dose before pregnancy was 0.102 +/- 0.009 mg per day; it was increased to 0.148 +/- 0.015 mg per day during pregnancy (P less than 0.01). The mean postpartum serum free-thyroxine index was 136.6 +/- 11.4 (P less than 0.05 as compared with values before and during pregnancy), and the mean postpartum serum thyrotropin level was 1.4 +/- 0.4 mU per liter (P less than 0.01 as compared with levels during pregnancy), demonstrating a decrease in the thyroxine requirement. The mean postpartum thyroxine dose was decreased to 0.117 +/- 0.011 mg per day (P less than 0.01 as compared with the dose during pregnancy). CONCLUSIONS: Our results indicate that the need for thyroxine increases in many women with primary hypothyroidism when they are pregnant, as reflected by an increase in serum thyrotropin concentrations. Although the effects of this modest level of hypothyroidism are not known, we think it prudent to monitor thyroid function throughout gestation and after delivery and to adjust the thyroxine dose to maintain a normal serum thyrotropin level.