Influence of nitrate in drinking water on the prevalence of thyroid cancer and other diseases (literature review and experience in post-chernobyl period in Belarus).

In the last 60 years dramatically increased the content of nitrates in groundwater due to intensive use of nitrogen fertilizers in agriculture. Research in post-Chernobyl period has shown that a sharp increase in the incidence of thyroid cancer depends not only on the level of thyroid dose, but also on the level of nitrates in groundwater.

The thyroid axis 'setpoints' are significantly altered after long-term suppressive LT4 therapy.

The aim of the study was to investigate the changes in the thyroid axis setpoint after long-term suppressive levothyroxine therapy for differentiated thyroid carcinoma and the resulting changes in levothyroxine requirement. Ninety-nine differentiated thyroid cancer patients were reviewed. All patients had at least one known TSH-level≥0.01 mU/l (lower detection limit) and <1.0 mU/l within 2 years of initial treatment (time 1) and had at least one TSH-value≥0.01 mU/l and <1.0 mU/l after continuous LT4 therapy for a minimum of 5 years (time 2).At time 2 the mean LT4 dosage/kg body weight, TSH, FT3, and FT4 levels were significantly lower than at time 1, while body weight was higher. At time 2, the FT3/FT4 ratio rate had dropped significantly (p<0.001). At time 1, patients would require 2.96 µg/kg body weight to reach total TSH suppression. The dose of levothyroxine/kg required for suppression can be lowered by about 0.05 µg/kg body weight for each year of suppressive therapy. After a median of 12.7 years of continuous suppressive levothyroxine therapy, patients would require 2.25 µg/kg body weight (-23.5%) to reach total TSH-suppression. At least part of this reduction was independent of aging. As a result of changes in thyroid hormone metabolism and thyroid axis setpoint, long-term TSH-suppressive therapy contributes to a reduction in the dosage of levothyroxine per kilogram body weight required for full TSH suppression over time.

Relationship between antithyroglobulin autoantibodies and thyroglobulin recovery rates using different thyroglobulin concentrations in the recovery buffer.

The aim of the work was to examine the relationship between thyroglobulin autoantibody (TgAb) levels and the Tg recovery rate (TgRR) using different concentrations of Tg (50, 10, 5, and 1 µg/l) in the recovery buffer. A total number of 225 serum samples from individual patients were analyzed. Samples were selected for their TgAb in 6 groups: TgAb1 000 IU/ml (n=28). TgAb were measured with 2 different assays (VARELISA and BRAHMS Anti-Tgn RIA). TgAb levels and the TgRR determined using the 50, 10, 5, and 1 µg/l buffers showed strong significant correlations with a Spearmans' rho of - 0.720, - 0.688, - 0.686, and - 0.356, respectively, for the VARELISA assay and - 0.670, -0.617, - 0.570, and - 0.274, respectively, for the Anti-Tgn assay (all p<0.001). TgRRs were a median of 94.8% (30.5-113.0%), 90.8% (40.6-127.6%), 90.0% (8.2-119.3%), and 89.4% (range - 43.6-121.6%) for the TgRR determined using recovery buffers with concentrations of 50, 10, 5, and 1 µg/l respectively. With decreasing Tg concentration in the recovery buffer the percentage of abnormal results increased, although the extreme increase we found in the 1 µg/l group is largely caused by a lack of analytical precision in the 73 sera with Tg levels exceeding 5 µg/l. Our results give cause for further investigation into reviving the concept of Tg-recovery measurement using 5 µg/l Tg in the recovery buffer instead of the traditional 50 µg/l.

Short-term severe thyroid hormone deficiency does not influence sleep parameters.

PURPOSE: The influence of short-term severe thyroid hormone deficiency on sleep is currently still unknown. Several studies have demonstrated an effect of long-term hypothyroidism on sleep disorders due to anatomical changes of the pharynx or body mass. The aim of this preliminary study, however, is to evaluate the changes in sleep patterns of patients with short-term hypothyroidism to elucidate the isolated effect of thyroid hormone withdrawal before anatomical changes can potentially occur. METHODS: Ten patients with differentiated thyroid carcinoma were enrolled in this study. Two patients discontinued the study and one patient was finally excluded due to obesity, so that the datasets of seven patients were available for study analysis. During the course of carcinoma treatment, each patient had previously undergone total thyroidectomy and I-131 remnant ablation. Polysomnographic measurements were performed twice: (1) over the course of two consecutive nights during severe thyroid hormone deficiency after levothyroxine withdrawal and prior to further diagnostics and therapy and (2) during euthyroidism after substitution with levothyroxine. RESULTS: Comparison of the Epworth Sleepiness Scale during hypo- and euthyroidism for each patient revealed no statistically significant difference. Furthermore, the comparison of polysomnographic parameters like (1) apnea-hypopnea index, (2) the duration of various sleep stages, (3) duration of rapid eye movement sleep, (4) latency until rapid eye movement sleep, (5) total sleep time, (6) periodic leg movements, and (7) arousal index showed no statistically significant differences between the hypothyroid or euthyroid state. CONCLUSIONS: We conclude that, in this preliminary experimental setting, short-term severe thyroid hormone deficiency per se does not cause sleep disturbances and a feeling of fatigue as described in other studies may be due to changes in perception or brain metabolism during hypothyroidism.

Evaluation of the BRAHMS KRYPTOR thyroglobulin "mini-recovery" test in thyroid healthy subjects.

The aim of the work was to compare the automated thyroglobulin (Tg) assay on the automated BRAHMS KRYPTOR platform (hTG KRYPTOR) to the established BRAHMS Tg Plus immunoradiometric assay for the measurement of Tg levels and regular Tg recovery rates and to assess a recovery test using a low Tg concentration of 10 µg/l ("mini-recovery") in samples with a native Tg level of <10 µg/l. Tg levels and recovery rates, as well as the mini-recovery, were determined in 208 serum samples from thyroid-healthy patients using both assays. The reference ranges for the Tg-Plus assay are 2.0-51.0 µg/l for Tg levels and 81.5-108% for recovery rates at 100 µg/l. The reference ranges for hTG KRYPTOR are 2.4-47.8 µg/l for Tg, 83.3-110.4% for a conventional recovery with 80 µg/l in Tg levels ≥ 10.0 µg/l (n=121) and 94.4-122.9% for the mini-recovery with Tg <10.0 µg/l (n=87). The correlation between the Tg-Plus and hTG KRYPTOR is excellent for Tg (r2=0.95; p<0.001), but not significant for recovery rates. Tg levels determined using the KRYPTOR Tg assay are clinically comparable to the conventional Tg-Plus assay. New features of the KRYPTOR assay such as the ability to perform a "mini-recovery" still require further study before clinical use.

Recombinant human thyrotropin: safety and quality of life evaluation.

Recombinant human TSH (rhTSH) (thyrotropin alfa, Genzyme Co.) has been developed to improve the management of patients with differentiated thyroid cancer, who need radioiodine (131I) for treatment or follow-up diagnosis. Data available from published series involving approximately 500 patients prove that rhTSH is safe and that mostly unspecific non-severe side effects may occur (e.g. nausea, vomiting, headache or fatigue and dizziness). Tumor swelling which has been occasionally observed after rhTSH injection is a phenomenon well known from the past attributed to endogenous TSH stimulation after thyroid hormone withdrawal (THW) and can be prevented or alleviated by concomitant administration of glucocorticoids. The absorbed dose to the tumor after preparation of 131I therapy with rhTSH as compared to THW is not statistically different. The radiation dose to the blood and the remainder, however, is significantly lower if rhTSH is used instead of THW which is a strong argument in favor of rhTSH. Most importantly, the quality of life (QOL) after rhTSH is preserved as compared to THW where symptoms of hypothyroidism significantly impair QOL. Last but not least, more convenient scheduling of patients and shorter duration of time to be spent in the radioprotective ward are further arguments in favor of rhTSH.

Reference ranges for analytes of thyroid function in children.

Promptly detecting pediatric thyroid dysfunction requires age-appropriate reference ranges for serum thyroid-stimulating hormone (TSH), serum free thyroxine (FT4), and serum free triiodothyronine (FT3). We sought to establish such ranges, employing the widely-used Immulite® 2000 automated immunoluminometric assays in a large population. We assayed the analytes according to manufacturer's instructions in serum samples from 359 male and 297 female university hospital patients, aged between newborn to 18 years, without evidence of thyroid or pituitary dysfunction. As data were not normally distributed, the reference ranges were assumed to lie between the 2.5th and 97.5th percentiles. Curves for age-related changes in the reference ranges were calculated using the linearity, median and skewness method. TSH, FT4, and FT3 reference ranges showed a wide spread immediately after birth, rapidly decreasing within the first 2 years of life. Reference range width was fairly stable after about age 4 years. However, from that time, the ranges' lower and upper limits steadily declined, essentially reaching (FT3) or approximating (TSH, FT4) healthy adult values by age 18 years. Age-specific reference ranges should be used when measuring TSH, FT4, and FT3 in children. During very early life, values of these analytes range widely, making it challenging to interpret measurements in infants, and, especially, newborns.

(131)I therapy in patients with benign thyroid disease does not conclusively lead to a higher risk of subsequent malignancies.

UNLABELLED: Due to its excellent tolerability and low incidence of side effects, 131I therapy has been the treatment of choice for benign thyroid diseases for over 60 years. A potentially increased risk of malignancies due to this therapy is however still subject of debate. AIM: To review the literature pertaining to 131I therapy of benign thyroid diseases in order to establish whether there is an increased incidence of, or increased mortality due to malignancies of the thyroid or other organs. METHODS: In order to allow for sufficient long-term follow-up time after 131I therapy, only literature after 1990 was reviewed. Two criteria were applied to consider an increased incidence of malignancies linked to 131I therapy: a) there should be a latency period of at least 5 years between 131I therapy and the observation of an increased risk b) an elevated risk should increase with increasing radiation exposure. RESULTS: A total of 7 studies reporting cancer incidence and / or mortality in 4 different patient collectives spanning a total of 54510 patients over an observation period varying from 2-49 years were found. Although some studies detected a slightly increased risk for malignancies of the thyroid or the digestive system, others did not find these effects - while other studies even reported a slightly lower risk of malignant (thyroid) disease after 131I therapy for benign thyroid diseases. CONCLUSION: As over 60 years of experience has thus far failed to produce conclusive evidence to the contrary, it can be concluded that there is no increased risk of malignancies after 131I therapy for benign thyroid disease.

[When is thyroid fine-needle biopsy most effective?]. / Wann ist die Feinnadelbiopsie der Schilddrüse am effektivsten?

The essentially desirable standardisation of various European and American guidelines for the evaluation of thyroid nodules has led to the recommendation to perform fine-needle biopsy (FNB) in all nodules >1 cm in order to detect clinically occult thyroid carcinoma early. However, in iodine-deficient areas such as Germany (where thyroid nodules are found in approximately 25% of the adult population) this recommendation would substantially increase both the number of FNB and thyroid operations without significantly increasing the cancer detection rate. The recommendation for FNB in Germany, therefore, should be restricted to hypofunctioning ("cold") nodules >1 cm.

Heterophile antibodies rarely influence the measurement of thyroglobulin and thyroglobulin antibodies in differentiated thyroid cancer patients.

The aim of the study was to determine the impact of heterophile antibodies on the measurement of serum thyroglobulin (Tg), thyroglobulin recovery, and thyroglobulin antibody levels in differentiated thyroid carcinoma patients. We studied serum samples of 201 individual patients that were followed in our hospital for differentiated thyroid carcinoma and 52 control samples. Samples were split; half were treated by incubating the sample for 1 h in HAB-blocking tubes, the remainder was left untreated. Subsequently thyroglobulin and thyroglobulin antibody levels were measured in both the blocked and untreated samples. A difference between the two samples was considered significant if the blocked sample deviated from the untreated one by more than 2.77 times the standard deviation for the method. In the measurement of Tg, 2 patients showed a moderate, but significant lowering of Tg levels after blocking treatment, but not so great as to affect clinical management. None of the 52 controls showed heterophile antibody interference in thyroglobulin measurement. Neither in DTC patients, nor in controls was any possible heterophile antibody interference encountered. And in all thyroid carcinoma patients, and in all but one controls, no interference was found in the thyroglobulin antibody measurement. All in all a possible heterophile antibody interference was found in 3/759 tests (0.4%). We can assume that heterophile antibody interference is not a factor to be reckoned with in the daily practice of Tg measurement in the treatment and follow-up of differentiated thyroid carcinoma patients.

The association between multinodular goiter and thyroid cancer.

In many parts of the world, especially those of current or former iodine deficiency, multinodular goiter is still an endemic disease. In this brief review several clinically relevant issues in the complex association between nodular goiter and differentiated thyroid cancer will be highlighted. There are some intriguing links between the etiologies of multinodular goiter and that of thyroid cancer. This could also influence the incidence of thyroid cancer in multinodular goiter. However, multinodular goiter causes extra difficulties in the diagnosis of differentiated thyroid cancer; these same difficulties also cause additional issues in thyroid cancer treatment in multinodular goiter patients. Last but not least it will be discussed whether there is a possibility to impede the development of thyroid cancer in multinodular goiter.

[Nuclear medical inpatient treatment in Germany - analysis of structured quality reports 2004-2008]. / Stationäre nuklearmedizinische Therapie in Deutschland - Analyse der strukturierten Qualitätsberichte 2004 bis 2008.

UNLABELLED: All public licensed hospitals of Germany are obligated since 2004 to establish and to publish a structured biennial quality report. The aim of this study was to analyse the quality reports from 2008 of clinics with nuclear-medicine therapy ward and to investigate developments for the inpatient nuclear-medicine therapy by comparing the results with the quality reports of the years 2004 and 2006. METHODS: All available structured quality reports of clinics with a nuclear-medicine therapy ward of the years 2004, 2006 and 2008 were evaluated. RESULTS: The total number of inpatient treatment cases in 2008 amounted to 54190 (2006: 54884; 2004: 57366). This corresponds to a decrease of 5.5% in comparison to 2004. The number of the therapy wards decreased at the same time to currently 117 (2006: 120; 2004: 124). Remarkable changes were found in the spectrum of the main diagnosis. Thus, the most frequent diagnosis with the ICD-code E05 (hyperthyroidism) decreased continuously from 37747 treatments in 2004 and 34764 in 2006 to 31756 in the year 2008. In contrast, the ICD-diagnoses for thyroid cancer (C73, Z08) with 14761 cases in 2008 increased with time (2006: 13426; 2004: 12581). CONCLUSIONS: In analogy to the observations from Europe after introduction of an iodine prophylaxis the improved iodine supply in Germany has led to a decline of the radioiodine therapy due to hyperthyroidism.

[Procedure guideline for sentinel lymph node diagnosis]. / Verfahrensanweisung für die nuklearmedizinische Wächter-Lymphknoten-Diagnostik.

The authors present a procedure guideline for scintigraphic detection of sentinel lymph nodes in malignant melanoma and other skin tumours, in breast cancer, in head and neck cancer, and in prostate and penile carcinoma. Important goals of sentinel lymph node scintigraphy comprise reduction of the extent of surgery, lower postoperative morbidity and optimization of histopathological examination focussing on relevant lymph nodes. Sentinel lymph node scintigraphy itself does not diagnose tumorous lymph node involvement and is not indicated when lymph node metastases have been definitely diagnosed before sentinel lymph node scintigraphy. Procedures are compiled with the aim to reliably localise sentinel lymph nodes with a high detection rate typically in early tumour stages. Radiation exposure is low so that pregnancy is not a contraindication for sentinel lymph node scintigraphy. Even with high volumes of scintigraphic sentinel lymph node procedures surgeons, theatre staff and pathologists receive a radiation exposure <1 mSv/year so that they do not require occupational radiation surveillance.

Thyroid cancer in infants and adolescents after Chernobyl.

Studies in children medically exposed to external irradiation more than 50 years ago revealed a considerably increased risk for thyroid cancer. Similarly, a strongly age-dependent risk for thyroid cancer was observed in the Japanese population after the atomic bomb explosions with the highest risk in the group of children below age of 10. After the Chernobyl accident, children from Belarus living in highly exposed regions received mean thyroid doses by radioactive fallout higher by a factor of approximately 2 as compared to the survivors of the atomic bomb explosions. This lead to a radiation related increase of thyroid cancer incidence in children and adolescents with the highest incidence in age group 0-4 years up to now totally amounting to approximately 5 000 cases. For screening of thyroid cancer in children, high resolution ultrasound is the method of choice which has to be complemented by fine-needle aspiration biopsy in suspicious cases. Diagnostic criteria for malignancy in childhood thyroid cancer by ultrasound are hypoechogenicity and irregularity of the outline, subcapsular location of lesions and increased peri-intranodular vascularisation. The treatment strategy for thyroid cancer in children does not differ substantially from the approach used in adults. Primary treatment consists of thyroidectomy and lymph node dissection. Careful and complete removal of the lymph nodes is of great clinical relevance in children because of very frequent node involvement (between 40% and 90%). Because of the high prevalence of lymph node metastases, ablation of thyroid remnants is mostly indicated in children with thyroid cancer. Distant metastases which need higher activities of radioiodine are less frequent with 10-20%. Even in advanced cases of childhood thyroid cancer, long-lasting remissions can be achieved. A specific finding in children is disseminated, milliary lung metastases with intense radioiodine uptake. In this situation, pulmonary fibrosis may be a severe side-effect so that the indication for repeated courses of radioiodine therapy has to be decided thoroughly. With respect to side-effects of radioiodine therapy, the risk of developing breast cancer has to be taken into account seriously since especially the female breast is exposed to a relatively high radiation dose. Generally, young patients treated with high activities of radioiodine should be carefully followed up during their whole lifespan.

[Procedure guideline for thyroid scintigraphy (version 3)]. / Verfahrensanweisung für die Schilddrüsenszintigraphie (Version 3).

The version 3 of the procedure guideline for thyroid scintigraphy is an update of the procedure guideline previously published in 2003. The interpretation of the scintigraphy requires the knowledge of the patients' history, the palpation of the neck, the laboratory parameters and of the sonography. The interpretation of the technetium-99m uptake requires the knowledge of the TSH-level. As a consequence of the improved alimentary iodine supply the (99m)Tc-uptake has decreased; 100,000 counts per scintigraphy should be acquired. For this, an imaging time of 10 minutes is generally needed using a high resolution collimator for thyroid imaging.

[Procedure guideline for radioiodine test (Version 3)]. / Verfahrensanweisung zum Radioiodtest (Version 3).

The version 3 of the procedure guideline for radioiodine test is an update of the guideline previously published in 2003. The procedure guideline discusses the pros and cons of a single measurement or of repeated measurements of the iodine-131 uptake and their optimal timing. Different formulas are described when one, two or three values of the radioiodine kinetic are available. The probe with a sodium-iodine crystal, alternatively or additionally the gamma-camera using the ROI-technique are instrumentations for the measurement of iodine-131 uptake. A possible source of error is an inappropriate measurement (sonography) of the target volume. The patients' preparation includes the withdrawal of antithyroid drugs 2-3 days before radioiodine administration. The patient has to avoid iodine-containing medication and the possibility of additives of iodine in vitamin- and electrolyte-supplementation has to be considered.

[Procedure guideline for radioiodine therapy and 131iodine whole-body scintigraphy in paediatric patients with differentiated thyroid cancer]. / Verfahrensanweisung zur Radioiodtherapie und 131I-Ganzkörperszintigraphie bei differenzierten Schilddrüsenkarzinomen im Kindes- und Jugendalter.

The procedure guideline for radioiodine ((131)I) therapy and (131)I whole-body scintigraphy of differentiated thyroid cancer in paediatric patients is the counterpart to the procedure guidelines (version 3) for adult patients and specify the interdisciplinary guideline for thyroid cancer of the Deutsche Krebsgesellschaft concerning the nuclear medicine part. Characteristics of thyroid cancer in children are the higher aggressiveness of papillary thyroid cancer, the higher frequency of extrathyroidal extension and of disseminated pulmonary metastases as well as the high risk of local recurrences. Radioiodine therapy is generally recommended in children, the (131)I activity depends on the children's body weight. Radioiodine ablation in children with small papillary cancer (< or =1 cm) should be considered. TSH stimulation is reached two weeks (children) or three weeks (adolescents) after withdrawal of thyroid hormones. Anti-emetic drugs are highly recommended. CT of the chest and examination of pulmonary function are clearly indicated if there is any suspicion on metastases. 3-6 months after (131)I ablation, the (131)I whole-body scintigraphy is highly recommended as lymph node metastases are frequently detected in paediatric patients. Follow-up care should be arranged in shorter intervals than in adults to test the compliance and to adapt dosage of thyroid hormones to the children's body weight. Reference values of fT3 are higher in children than in adults. Evidence is insufficient to describe in which constellation the TSH may be kept within the low normal level. Therefore, TSH suppression is generally recommended.

[Procedure guideline for iodine-131 whole-body scintigraphy for differentiated thyroid cancer (version 3)]. / Verfahrensanweisung für die Iod-131-Ganzkörperszintigraphie beim differenzierten Schilddrüsenkarzinom (Version 3).

Version 3 of the procedure guideline for (131)I whole-body scintigraphy (WBS) is the counterpart to the procedure guideline for radioiodine therapy (version 3) and specify the interdisciplinary guideline for thyroid cancer of the Deutsche Krebsgesellschaft concerning the nuclear medicine part. (131)I WBS 3-6 months after (131)I ablation remains a standard procedure in an endemic area for thyroid nodules and the high frequency of subtotal surgical procedures. Follow-up without (131)I WBS is only justified if the following preconditions are fulfilled: low-risk group pT1-2, pN0 M0 with histopathologically confirmed pN0, (131)I uptake <2%, (131)I WBS during ablation without any suspicious lesion, stimulated thyroglobulin (Tg)-level 3-6 months after ablation <2 ng/mL, and absence of anti-thyroglobulin-antibodies with normal recovery-testing. If patients from the low-risk group show normal (131)I WBS 3-6 months after ablation and stimulated Tg is of <2 ng/mL, there will be no need for additional routine (131)I WBS. If patients from the high-risk group show normal (131)I WBS and stimulated Tg-level of <2 ng/mL 3-6 months after ablation, the follow-up care should include repeated stimulated Tg-measurements. If the Tg-level remains below 2 ng/mL, an additional (131)I WBS will be not necessary. The recommended intervals for stimulated Tg-testing are adapted to the prior intervals for (131)I WBS-testing in the high-risk group. Increased anti-thyroglobulin-antibodies or incomplete recovery-testing make an individual strategy of follow-up care necessary, which include (131)I WBS.

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.