Malignancy rates in thyroid nodules: a long-term cohort study of 17,592 patients.

Objectives: Ultrasound diagnosis of thyroid nodules has greatly increased their detection rate. Their risk for malignancy is estimated between 7 and 15% in data from specialized centers which are used for guidelines recommendations. This high rate causes considerable anxiety to patients upon first diagnosis. Here, we retrospectively analyzed the malignancy rate of sonographically diagnosed nodules larger than 1 cm from a primary/secondary care center when long-term longitudinal follow-up was included. Patients/methods: In the study, 17,592 patients were diagnosed with a thyroid nodule larger than 1 cm, of whom 7776 were assessed by fine-needle aspiration cytology (FNAC) and 9816 by sonography alone. 9568 patients were initially discharged due to innocent results of FNAC and/or ultrasound. In 1904 patients, definitive histology was obtained, and 6731 cases were included in the long-term follow-up (up to 23 years, median 5 years). Results: Malignancy was histologically confirmed in 189 patients (1.1% of all) when excluding accidentally diagnosed papillary microcarcinomas. 155 were diagnosed during the first year of management, 25 in years 2-5 of follow-up, 9 in years 6-10 and nil in 1165 patients followed beyond 10 years. Conclusions: The malignancy rate of thyroid nodules from primary/secondary care was much lower than that previously reported. During follow-up for more than 5 years, their rate rapidly dropped to less than 1/1000 cases. This low malignancy rate may help to reassure patients first confronted with the diagnosis of a thyroid nodule, substantially reduce their anxiety and avoid unwarranted diagnostic and therapeutic procedures.

Age and sex as predictors of biochemical activity in acromegaly: analysis of 1485 patients from the German Acromegaly Register.

OBJECTIVE: We evaluated the German Acromegaly Register for clinical variables associated with the initial biochemical activity of patients with acromegaly. DESIGN: Retrospective analysis of data in the registry. PATIENTS: A total of 1485 patients with acromegaly (males 45.6%, females 54.4%) were treated in 42 German endocrine centres until November 2005. Linear regression models were used to estimate the influence of various parameters on biochemical activity. RESULTS: Male patients with acromegaly were significantly younger at the time of diagnosis than female patients (41 vs. 47 years, P < 0.0001) and had significantly higher random GH levels than females (21 vs. 14 ng/ml, P < 0.005) and IGF-1 levels (773 vs. 679 ng/ml, P < 0.0001), respectively. Age at initial presentation turned out to be the most important independent risk factor associated with random GH levels, oral glucose tolerance test-suppressed GH levels, IGF-1 levels, body mass index (BMI), tumour size and prevalence of hypopituitarism. Sex was an independent risk factor for IGF-1 levels, BMI and prevalence of hypopituitarism. Tumour size was an independent risk factor for both GH and IGF-1 levels. CONCLUSIONS: In summary, initial biochemical activity of acromegaly is influenced by patient's age and to a lesser degree by patient's sex. Male patients are on an average 6 years younger than females.

A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A.

One hundred and eighty-one families with multiple endocrine neoplasia type 2A (MEN-2A) or familial medullary thyroid carcinoma (FMTC) have been investigated for mutations in the ret protooncogene in Germany. In 8 families with FMTC or MEN-2A, no mutation could be detected in the cysteine-rich domain encoded in exons 10 and 11 of the ret protooncogene. DNA sequencing of additional exons (no. 13-15) revealed rare noncysteine mutations in 3 families (codons 631, 768, and 844). In contrast to these rare events, heterozygous missense mutations in exon 13, codons 790 and 791, were found in 5 families (4 with MTC only; 1 family with MTC and pheochromocytoma) and 11 patients with apparently sporadic tumors. Two different mutations in codon 790 (TTG-->TTT, TTG-->TTC; Leu790Phe) and one mutation in codon 791 (TAT-->TTT; Tyr791Phe) created a phenylalanine residue. We conclude that codons 790 and 791 of the ret protooncogene represent a new hot spot for FMTC/MEN-2A causing mutations. With the discovery of these considerably common mutations in codons 790 and 791 and the identification of some rare mutations, 100% of the German FMTC/MEN-2A families could be characterized by a mutation in the ret protooncogene.

Nerve growth factor (NGF) sensitizes human medullary thyroid carcinoma (hMTC) cells for cytostatic therapy in vitro.

Medullary thyroid carcinoma (hMTC) cells were established from nine patients with MTC disease to initiate a new approach of adjuvant medical therapy in these patients. We measured calcitonin (CT) secretion, DNA synthesis, and cell proliferation in vitro and their response to various substances. Nerve growth factor (NGF) (0.01 to 10 micrograms/ml), glucagon (0.01 to 100 micrograms/ml), and isoproterenol (4 to 500 micrograms/ml) stimulated CT secretion and DNA synthesis in hMTC cells. Other substances, calcium (1.0 to 15 mmol), pentagastrin (1.0 to 50 mumol), dibutyryl-cyclic-adenosine-monophosphate (1.0 to 100 mumol), and phorbol ester TPA (1.0 to 100 nmol), stimulated CT secretion but not DNA synthesis. In addition, NGF enhanced cell proliferation of hMTC cells 2- to 3- fold and caused an increased sensitivity of these cells for chemotherapy in vitro. Thus 0.5 microgram/ml doxorubicin (half-maximal effective dose) induced a cell death rate of up to 32.8%, which was enhanced by preincubation with NGF to 68.1% (1.0 microgram/ml, NGF) and to 100% (10.0 micrograms/ml, NGF), respectively. Pulsative stimulation of APUD cell carcinomas with NGF may therefore improve the response rate of these tumors to chemotherapy, which would be of significant clinical importance for patients with residual postoperative MTC tissue.

Radioimmunoassay for 3,3'-diiodothyronine in human serum.

A specific radioimmunoassay for measurement of 3,3'-diiodothyronine (T2') is presented. With the method described (ethanol extraction of native serum and lyophilisation of the extract) the application of 400 microliter serum equivalent in the assay is possible. Standards and sera are treated similarly. The detection limit is 0.625 ng/dl, comparison between direct assay and dried extract assay shows good correlation. Mean normal T2' serum concentration in man is 7.2 ng/dl (range 3 to 11 ng/dl), hypothyroid: below 3.0 ng/dl, hyperthyroid: 11-64 ng/dl (range). T2' level in cord-blood of newborns: 16.5 ng/dl. The urinary excretion of free T2' of normal man is 0.49 microgram/24 h (mean), a relatively high excretion rate in comparison to the low serum level.

Investigations on the deiodination of thyroxine (T4) to 3,3'-diiodothyronine (3,3'-T2) in rat liver homogenate.

Properties of an inactivating pathway of T4 to 3,3'-diiodothyronine (T2') in rat liver homogenate are described. The intermediate product (of this reaction sequence) is reverse T3 (rT3) which is very labile and cannot be measured at pH 7.5. The apparent KM of the reaction rT3 to T2' is 2 X 10(-8) M. The activities catalyzing the reactions T4 to T3, T4 to T2' and rT3 to T2' are found in the 100 000 X g pellet. Propylthiouracil inhibits all three activities to a similar degree; alpha-methyl-p-tyrosine has no effect. T3 seems to be only a minor source of T2' production. The molar ratio of the two T4 deiodination pathways T4 to T3/T4 to T2' under these conditions is about 1.7; however, by changing the pH this ratio could be significantly altered.

Induction of the thyroxine (T4) to triiodothyronine (T3) converting enzyme in rat liver by thyroid hormones and analogs.

In thyroidectomized, unsubstituted rats the T4 to T3 converting activity of liver homogenate is reduced to about 30% of that in unoperated control animals. The enzyme activity can be reinduced dose-dependently with T4. To achieve a normal activity, high, non-physiological plasma T4 concentrations are needed. Plasma T3 levels are much better correlated to the T4 to T3 converting activity. Pure T3 proved to be a more potent enzyme inducer than T4. No difference could be detected between L- and D-T3. Tyrosine, diiodotyrosine, 3,3'-diiodothyronine and 3,3',5'-T3 (reverse-T3) showed no inductive effect for the enzyme. These results demonstrate that the T4 to T3 converting enzyme is specific and shows regulatory properties.

Radioimmunoassay for 3,3',5'-triiodothyronine (reverse T3, R-T3) in unextracted human serum.

Highly specific antibodies against 3,3',5'-triiodothyronine (reverse T3, R-T3) have been produced in rabbits. The crossreaction with T4 is about 0.05%. A radioimmunoassay for R-T3 in unextracted serum was developed. ANS is used for blocking the binding of tracer and endogenous R-T3 to TBG. The sensitivity to the assay is 0.06 ng/ml plasma. The mean normal R-T3 concentration is 0.20 ng/ml. Thyrotoxic patients show elevated levels; in most hypothyroid patients R-T3 concentrations are below the detection limit.

Properties of the thyroxine (T4) monodeiodinating system in rat liver homogenate.

The monodeiodination of T4 in rat liver homogenate was studied. The two possible products of this reaction show very different properties. The metabolically very active T3 is rather stable in this system whereas the biological inactive reverse T3 (rT3) disappears very rapidly. This explains the low apparent rT3 production in the incubation mixture even under optimal conditions and the peculiar pH profile. The T4 to T3 converting reaction can be increased by the addition of mercaptoethanol to the medium; no further activation is possible by several cofactors tested. The apparent KM of the reaction is 1.6 x 10(-6) M. Reverse T3 does inhibit the reaction non competitive; Ki = 2 x 10 (10-8) M. Alpha-methyl-para-tyrosine, a specific inhibitor of tyrosine hydroxylase, has no significant effect on the reaction.

Calcitonin measurement to detect medullary thyroid carcinoma in nodular goiter: German evidence-based consensus recommendation.

Serum calcitonin (CT) has become a very specific and sensitive marker for human medullary thyroid carcinoma (MTC), a neuroendocrine tumor affecting about 1 % of patients with nodular thyroid disease. MTC is characterized by early micrometastasis and a lack of curative non-surgical treatment, so that early diagnosis is desirable. Based on a systematic review of scientific evidence, we propose multidisciplinary consensus recommendations for the clinical use of CT in patients with nodular goiter. To exclude MTC, serum CT should be determined in patients with nodular thyroid disease, using a two-site CT immunoassay. If basal serum CT exceeds 10 pg/ml, CT should be analysed by pentagastrin stimulation testing, after renal insufficiency and proton pump inhibitor medication have been ruled out. As the risk for MTC is higher than 50 % in patients with stimulated CT values > 100 pg/ml, thyroidectomy is advised in these individuals. If stimulated CT exceeds 200 pg/ml, thyroidectomy and lymphadenectomy is strongly recommended. Pentagastrin-stimulated CT values < 100 pg/ml are associated with a low risk of MTC, or very rarely, non-metastasizing micro-MTC (size < 10 mm). Therefore, regular clinical and biochemical follow-up is the preferred treatment in such patients, unless thyroid malignancy is suspected otherwise.

[Subtotal thyroidectomy as a superior therapeutic principle in the treatment of endocrine ophthalmopathy: a comparison with retrobulbar irradiation and thyrostatic therapy alone]. / Subtotale Thyreoidektomie als überlegenes Therapieprinzip bei der Behandlung der endokrinen Ophthalmopathie: Ein Vergleich mit Retrobulbärbestrahlung bzw. alleiniger thyreostatischer Therapie.

In order to investigate the influence of near total thyroidectomy on the course of endocrine ophthalmopathy (E.O.) in patients with Graves' disease, 29 patients with goitre and E.O. were classified before and after (up to 18 months) operation by use of a special ophthalmopathy index. 14 patients without goitre served as controls; they get only antithyroid drug treatment (ADT) (E.O. I and II, n = 7) or additional retoorbital irradiation (E.O. III and IV, n = 7, linear accelerator, 20 Gray). 20 out of 29 operated patients showed an improvement in the E.O., 4 a deterioration, 5 were unchanged. 3 out of 7 not operated patients with mild E.O. showed an amelioration during ADT, 4 no change. Additional radiotherapy in 7 patients with severe E.O. caused an improvement in the clinical condition of 3 patients, 3 patients deteriorated and 1 patient showed no change. It is concluded that adequate near total thyroidectomy has a positive effect on the clinical course of E.O. in patients with Graves' disease and E.O.

[Acute abdomen in unrecognized hyperparathyroidism]. / Das akute Abdomen beim nichterkannten Hyperparathyreoidismus.

The incidence of acute abdomen in patients with unrecognised hyperparathyroidism (HPT) was investigated in 61 patients with primary and 15 patients with secondary HPT, operated on at the Surgical University Department in Düsseldorf between 4/86 and 10/87. In seven patients (9%) an acute abdomen occurred preoperatively (bleeding ulcer n = 3, ulcer perforation n = 1, acute pancreatitis n = 3). Recurrent gastrointestinal disease was observed in 20 of the 76 Patients (28%). The fast and surprising clinical recovery of patients with pancreatitis and HPT after operation of the HPT support the assumption of a causal relation between hyperparathyroidism and pancreatitis. The importance of hypercalcaemia and HPT as causative factors in gastrointestinal ulcers, remains uncertain, however. Possible acute abdominal emergencies in the clinical course of primary hyperparathyroidism support the indication for early operation.

[Various strategies in the diagnosis and therapy of thyroid gland cancer. Results of a survey]. / Unterschiedliche Strategien in Diagnostik und Therapie des Schilddrüsencarcinoms. Ergebnis einer Umfrage.

In a questionnaire we compared generally adviced therapeutical and technical procedures in patients with thyroid carcinomas with the actually favorized strategy of the clinically active surgeons. At present, sonography and cytology are not favored as preoperative diagnostic tools by the questioned surgeons. Hemithyreoidectomy as primary procedure in suspicious nodules is performed only seldomly. In the treatment of thyroid carcinoma total thyroidectomy is the accepted procedure and the possibility of restricted radicality in the treatment of papillary thyroid carcinomas has gained wide acknowledgement. Most surgeons prefer to visualize the recurrent nerve and at least one or two parathyroid glands. Autotransplantation of parathyroid glands with insufficient blood supply is considered only seldomly.

[Therapy of euthyroid iron deficiency goiter. Effectiveness of a combination of L-thyroxine and 150 micrograms iodine in comparison with mono-L-thyroxine]. / Therapie der euthyreoten Jodmangelstruma. Wirksamkeit der Kombination aus L-Thyroxin und 150 micrograms Jodid im Vergleich zu Mono-L-Thyroxin.

BACKGROUND: In terms of the pathomechanism, TSH and intrathyroid iodine deficiency are the interconnecting elements between alimentary iodine deficiency and the growth and genesis of goiter. L-Thyroxine treatment for suppression of hypophyseal TSH production and supplementary iodide have a synergistic effect in reducing the size of goiter. An individual adaptation of the L-Thyroxine dose is necessary for optimal TSH suppression. Excessive suppression of the TSH level prevents uptake of iodine by the thyroid and thus compensation of the intrathyroid iodine deficiency. Combination therapy of an individually adjusted amount of L-Thyroxine with a small, mostly constant amount of iodine is a recognized concept of goiter therapy today. Administration of a combination preparation with an individually adjustable dose of L-Thyroxine and 150 micrograms iodine complies with these recommendations and improves compliance since only one tablet is required. PATIENTS AND METHODS: In the present study, the thyroid iodine supply, efficacy and tolerance of such a combination preparation was tested for the first time in 49 patients with euthyroid iodine deficiency goiter (group A). 45 patients receiving an individual L-Thyroxine therapy served as controls (group B). RESULTS: Supplementation of individually dosable L-Thyroxine with 150 micrograms iodide leads to a markedly raised iodine excretion in the urine (p < 0.005). This is an indirect indication of an improved thyroid iodine supply. Patients of group A showed a greater reduction of the thyroid volume (18.5% as compared to 16.8%, p = n. s.) and a more persistent TSH suppression (lowering by 39% [group A] as compared to a rise of 17% [group B]) in relation to the initial value (p < 0.004). This is attributable to the improved supply of iodine. CONCLUSION: The combination therapy tested was tolerated just as well as the mono-L-Thyroxine treatment with better efficacy.

Reduction of thyroid nodule volume by levothyroxine and iodine alone and in combination: a randomized, placebo-controlled trial.

CONTEXT: Nodular goiter is common worldwide, but there is still debate over the medical treatment. OBJECTIVE: The objective of the study was the measurement of the effect of a treatment with (nonsuppressive) T(4), iodine, or a combination of both compared with placebo on volume of thyroid nodules and thyroid. DESIGN: This was a multicenter, randomized, double-blind trial in patients with nodular goiter in Germany [LISA (Levothyroxin und Iodid in der Strumatherapie Als Mono-oder Kombinationstherapie) trial]. SETTING: The study was conducted in outpatient clinics in university hospitals and regional hospitals and private practices. PARTICIPANTS: One thousand twenty-four consecutively screened and centrally randomized euthyroid patients aged 18-65 yr with one or more thyroid nodules (minimal diameter 10 mm) participated in the study. INTERVENTION: Intervention included placebo, iodine (I), T(4), or T(4)+I for 1 yr. T(4) doses were adapted for a TSH target range of 0.2-0.8 mU/liter. OUTCOME MEASURES: The primary end point was percent volume reduction of all nodules measured by ultrasound, and the main secondary end point was a change in goiter volume. RESULTS: Nodule volume reductions were -17.3% [95% confidence interval (CI) -24.8/-9.0%, P < 0.001] in the T(4)+I group, -7.3% (95% CI -15.0/+1.2%, P = 0.201) in the T(4) group, and -4.0% (95% CI -11.4/+4.2%, P = 0.328) in the I group as compared with placebo. In direct comparison, the T(4)+I therapy was significantly superior to T(4) (P = 0.018) or I (P = 0.003). Thyroid volume reductions were -7.9% (95% CI -11.8/-3.9%, P < 0.001), -5.2% (95% CI -8.7/-1.6%, P = 0.024) and -2.5% (95% CI -6.2/+1.4%, P = 0.207), respectively. The T(4)+I therapy was significantly superior to I (P = 0.034) but not to T(4) (P = 0.190). CONCLUSION: In a region with a sufficient iodine supply, a 1-yr therapy with a combination of I and T(4) with incomplete suppression of thyrotropin reduced thyroid nodule volume further than either component alone or placebo.